New in Emedgene V37.0 (February 20, 2025)

Release highlights for V37.0 pipeline and workbench

• New CNV cytogenetic interpretation features! Genome and chromosome view with karyogram, many new significance, population and lab data tracks on the variant visualization, a new and improved version of the embedded IGV, and del/dup ISCN and cytobands annotations for easy reporting.

• Emedgene now supports a seamless cytogenetics visualization, interpretation, curation and reporting flow for Illumina arrays, in combination with DRAGEN array’s newly released CNV caller.

• Updates to the automated ACMG classification module for SNVs. The overall classification, PP3/BP4, PM2/BS1/BA1 are updated to the latest guidelines with significantly improved evidence. The user interface and traceability of modifications by users has also been improved.

• New granular filtering capabilities added on prediction scores, AF, VCF filter and user actions, including the ability to filter on variants that have not been viewed by the current user. This will enable labs to progressively reduce the number of variants appearing in presets and save time per case.

  • When applying a custom preset on the fly, the search for genes will restrict the analysis, rather than applying an OR as before.

• Self-serve: Customers can empty trash for cases in Move to Trash status, attach PONs to their kits and download their kit BED files independently of support teams.

• Annotations and Quality

  • For GRCh38, updated to gnomAD SV 4.1

  • SpliceAI update and addition of distance data

  • For STRs, added allele distribution in the quality tab

• Voice of Customer

  • New protein domain visualization track

  • Customize disease name for reporting

  • Emedgene Curate now displays number of variants/genes

  • Storage integration with Google Cloud

  • Added reporting fonts for Japanese and Thai

Emedgene customers can select their preferred version out of any of the past 5 releases. Customers on v32.0 and below should select an upgrade path at this time.

New CNV/cytogenetic interpretation features!

Get an easy view of the full genome and chromosome, which includes a karyogram, and LogR/TNS, BAF and LOH tracks. Make more informed variant interpretation decisions using the many new visualization tracks we’ve added to the updated embedded IGV interface. Streamline reporting with new del/dup ISCN and cytobands annotations.

New Genome View tab

The Genome View Tab is a powerful feature designed to give users a clear, visual overview of the Copy Number Variation (CNV) events and regions of homozygosity/loss of heterozygosity (ROH/LOH) across the genome for customers interpreting WGS, WES or array data. Segments are color coded based on type - blue for DEL; red for DEL, gold for LOH.

The genome view contains an ideogram and 3 tracks: the LogR (array) or TNS (NGS), a BAF and LOH/ROH.

Users can filter the displayed segments by size.

On the ideogram, users can click on chromosomes to switch to a per-chromosome view. Clicking on any variant within the ideogram will bring up the full variant page while hovering on it will show a popup with additional information.

Updated embedded IGV version for improved accuracy when zooming out

Illumina fixed a limitation of IGV web where when zooming out beyond 3Mbp, IGV used to perform a mean calculation, resulting in unclear BAF and BIGWIG tracks. It now displays the data accurately even when zooming out to the full genome.

Many new visualizations tracks are available on the embedded IGV!

This version adds 7 new visualization tracks for easy interpretation of copy number variants in Emedgene. This is in addition to all existing tracks. To improve usability, each track setting is optimized with redefined height and reference lines. In addition, the variant range is highlighted across all tracks.

Knowledge base tracks

• OMIM Track: An OMIM track will display genes associated with disease/s. Clicking an entity will show disease name and OMIM ID, associated gene and inheritance mode. A link to the relevant OMIM page is also available.

• ClinGen Dosage Sensitivity Track: The ClinGen track will display genes/regions with dosage sensitivity scores for Haploinsufficiency and Triplosensitivity of 1 (Little evidence), 2 (Emerging evidence), 3 (Sufficient evidence), or 40 (Dosage sensitivity unlikely), with color coding based on score severity. Clicking an entity will reveal genomic details, ClinGen scores, descriptions, and a link to the ClinGen database.

Population data tracks to provide structural variant frequency data

• gnomAD SV: Clicking a variant will display allele count (AC), allele frequency (AF), total alleles genotyped (AN), and population-specific data for AFR, AMR, EAS, EUR, and OTH groups.

• DGV: Clicking a variant will display ALT type (DEL or DUP), non-reference allele count, allele frequency, total alleles genotyped, and the variant ID for further reference.

• Decipher: Clicking a variant will display ALT type, allele count, frequency, total genotyped alleles, and variant ID, helping in case interpretation.

Lab historic data tracks

• The lab proprietary historic data track/s are now included in the variant page visualization, in addition to the existing capability to visualize Curated data tracks. This is the same data each case is annotated with. Clicking a variant will display variant type (SNV or CNV), chromosome position (+ end for CNV), het, hom, hemi, AF, last 10 samples.

General

• Immediately under the RefSeq track we have added a Protein domain visualization track, using data from Uniprot GRCh38 with a liftover to GRCh37. Clicking a domain will display Name, start, end, ID and link out to UniProt.

New annotations – cytobands & DEL/DUP ISCN

This version adds cytoband annotation for every variant in the system, as well as ISCN nomenclature for DEL and DUP.

The information is now available for every Variant Page, under Clinical Significance – Variant info and can be populated to reports.

SV population statistic filters

The new SV population databases – gnomAD SV, DGV, Decipher – have also been added to the population statistics filters and enable filtering on allele frequency, allele count and hom/hemi ratio thresholds.

Limitations

Currently the Genome Overview tab display is limited to the 500 largest variants. This limitation will be improved in an upcoming hotfix.

Fixed Issues

Variant Page | Visualization | IGV component no longer performs a mean calculation when zooming out by default, which previously occurred around 3Mbp.

Support for cytogenetic arrays

V37 introduces a full integration with the DRAGEN Array V1.2 caller for Cytogenetics workflows.

This will allow user sto run end-to-end cyto array workflows starting from BSSH and ICA, and connecting directly to Emedgene for tertiary analysis and reporting.

Add New Case now supports Array Case Type

Customers can now create array cases and bring the different array outputs – VCF, quality files and visualization files.

When creating your case (from UI, batch or API), a new case type for ‘Array’ is available. This automatically sets the Region of Interest BED file option to “No Filters”.

Calling DEL, DUP and LOH segments with DRAGEN Array

Customers can now ingest VCFs coming from DRAGEN Array V1.2 – Cyto caller. The reported segments will show up in the Analysis Tools, new Genome View, and in IGV visualization tab.

Support bedgraph files for visualization

Customers can upload (from batch/API) the sample’s associated bedgraphs for LogR and BAF that will later be used in the visualization modules in the Genome View and IGV.

Use array quality metrics

Each sample is associated with the following quality scores: Quality, Sex estimation, Autosomal Call Rate, Call Rate and LogR dev.

• The quality score is defined “High” when sample's Call Rate is equal or greater than 0.99 AND sample's LogR is equal or smaller than 0.2.

• Otherwise, it will be defined as “Low”.

The full information is shown in Lab tab for Array cases, under the Sample Quality section.

All new ACMG user interface, and updated automated classification module for SNVs

The ACMG SNV classification automation has been updated to adhere to the latest guidelines for the PP3, BP4, PM2, BS1 and BA1 tags as well as the overall classification calculation. Based on user feedback, we have a new user interface for the component which makes it easier to understand tag status and user modifications at-a-glance. Finally, we’ve added a new functionality to reclassify ACMG tags using the latest case data.

All new ACMG automated classification for SNVs user interface

The user interface of the ACMG SNV classification component has been refreshed for an easier at-a-glance view of the classification. The pathogenic and benign components have been separated, and the visibility of the applied strength per tag has been improved. ACMG tags will now have visible traceability for all user actions. Any manual change to a tag question, strength and status will be highlighted with the user icon. The user can compare the original results vs the user changes and review the live update of the variant ACMG classification and score.

ACMG Reclassify

ACMG classification will now have a new capability to reclassify ACMG using the case data. This new ability should help when reanalyzing old cases using new pipelines, where the user classification will not be overridden automatically by the reanalysis. You can reclassify to check the output of the automated component with the new annotation data, and also cancel to maintain original classification.

PP3 + BP4 update

A recent study by Pejaver et al. (2022) has introduced new frameworks for calibrating in silico prediction tools to ensure consistent application in clinical variant interpretation. This study proposed specific REVEL score thresholds for missense variant prediction for assignment of PP3 and BP4 strengths BP4: Very Strong <0.003, Strong 0.003-0.016, Moderate 0.016-0.183, Supporting 0.183-0.290; PP3: Supporting 0.644-0.773, Moderate 0.773-0.932, Strong >0.932. In addition, Walker et al. (2023) recommended applying a similar threshold-based approach for splicing predictions using SpliceAI, with thresholds set at 0.1 for BP4 and 0.2 for PP3. This allows for the appropriate weighting of computational evidence for splicing-impact predictions in addition to missense prediction.

Following these recommendations, these thresholds have been adopted in this Emedgene version, and the logic for assigning PP3 and BP4 has been updated to ensure more accurate, consistent, and evidence-based variant classification.

PM2 + BS1 update

In this version, the logic for BS1 and PM2 tags has been improved by implementing gene-specific allele frequency thresholds. These thresholds are determined based on known ClinVar variant allele frequencies for the gene and the disease’s mode of inheritance.

For BS1, the tag is now automatically calculated and enabled if the variant's allele frequency exceeds the established gene-level threshold. The BS1 tag will not be applied together with BA1 to avoid conflicts in classification. The gene-specific threshold is calculated using the maximum population frequency of all ClinVar pathogenic or likely pathogenic variants with at least one-star review status in the gene.

For PM2 in genes associated with autosomal dominant (AD) diseases, the frequency threshold is always set at 0.01%. For autosomal recessive (AR) genes, the threshold is set at 1% if ClinVar data is unavailable. When ClinVar data is available, the threshold is determined by the highest allele frequency of the most common P/LP variant with at least one-star status in ClinVar (using continental allele frequencies). If this frequency exceeds 1%, a 1% threshold is applied to prevent assigning PM2 to common variants. When no data is available, the default threshold remains 1%.

This update ensures that the logic for BS1 and PM2 is more accurate and tailored to each gene’s characteristics and clinical significance, improving the consistency and reliability of variant interpretation.

SNV ACMG overall classification automation logic update

In this version, we enhanced the overall variant classification calculation following the full ACMG tagging process. To reduce bias, similar criteria are no longer counted twice, and the weight distribution among ACMG tags was adjusted. Additional rules were incorporated to improve the accuracy and consistency of the final variant classification according to the latest recommendations.

• PP3 and PM4 are not counted with PVS1 (Abou Tayoun et al., 2018).

• PP5 and BP6 are not considered in the final classification (Biesecker et al 2018) unless manually applied by the user.

• PM2 has been downgraded to Supporting strength (PM2_SVI , 2020).

• PM1 + PP3 are capped to Strong (Pejaver et al. 2022).

Known Issues

Variant Page | ACMG Automation | Reclassify is only available for cases that were run with pipeline v37.0, reclassify button might be visible for cases not eligble.

Variant Page | ACMG Automation | Evidence text might not be accurate when new no double dipping logic is enabled.

Variant Page | ACMG Automation | When manually changing a tag status from inactive to active and back again, tag status might be incorrect.

New filtering capabilities – user actions & prediction scores

More filtering capabilities have been added based on customer feedback. The user actions filters have been organized and enhanced, with a new viewed/unviewed filter which allows labs to reduce the variants seen in progressive filters. A new missense prediction category has been added as well as enhanced population statistics and the ability to filter on the VCF filter status. Emedgene added a new ability to intersect on the fly search with existing filters or presets.

User action filters

Under the ‘Evidence & tags’ filter section, in simple mode the user can apply basic filters based on the follow user actions: all tags by current user, all tags by AI shortlist, all viewed variants and all un-viewed variants by the current user.

In the advanced mode, the user can apply specific more filters such as view variants assigned a specific pathogenicity, variants tagged by a specific tag by users, or by AI shortlist.

All these new filters are available to be used within presets.

‘Viewed’ filter was highly requested by customers. By applying this filter in progressive preset filters, users can review variants only once, and reduce the overall number of variants to review.

In silico prediction filters

A new & comprehensive set of filters on in-silico prediction scores has been added, as many users utilize these within their SOP. In simple mode these enable filtering on the overall missense prediction, conservation prediction and splice prediction presented in the In Silico Predictions card on the Variant Page.

In advanced mode, users can filter on:

• Revel scores between 0-1

• PrimateAI3D predictions of Benign or Damaging

• Z-missense values of -8 to 8

• PLI scores between 0 and 1

• GERP-RS values between -12.36 to 6.18

• SpliceAI DS AG, SpliceAI DS AL, SpliceAI DS DG and SpliceAI DS DL values between 0 and 1

Population statistics SV databases and enhancements

Under the ‘Polymorphism’ filter section advanced mode, Emedgene added the capability to apply SV population statistics databases (DGV, Decipher, gnomAD SV). These new filters are available to be used within presets as well.

For Allele frequency filters, Emedgene changed the possible resolution of the filter to a 0.0001 increment. Allowing users to apply the exact allele frequency filtration they desire per database.

VCF filter

Under the ‘Quality’ filter section advanced mode, Emedgene added a new filter ability based on the VCF ‘Filter’ field. Possible filtering option includes ‘Pass’ or ‘Other values’. Using this filter enables users to filter based on the direct VCF quality parameters.

Search intersect

When applying presets, users requested a capability to perform a sub-filtration on top of the existing applied filtering. Therefore, Emedgene applied a new filtering strategy where once applying a search filter, will create a real time sub-filtration on the preset results.

For example, when a preset is using a gene list based on multiple genes that returns many variants, a user can apply a search filter over the preset for a single gene that is part of that gene list, and the results will return only variants located on that single gene (results can be saved as a Custom Preset if needed).

Limitations

Analysis Tools | Presets | Preset filters v1 schema is deprecated, please upgrade to V2 prior to moving to this version.

Analysis Tools | Filters | DRAGEN SV caller contains a discrepancy between the VCF filter column and format field.

Known Issues

Analysis Tools | Filters | Filtering on prediction scores will intermittently not work for panel cases. Hotfix planned.

Self-Serve: Empty Trash, Attach PON to kit

Every Emedgene release enhances customer control over their account, and reduces reliance on Illumina tech support for account configuration and maintenance.

Empty Trash

In V35.0 we added a new case status 'move to trash' where users can mark cases that they would like to delete from their organization. In this version, we are adding the ability to empty the Trash folder.

The Cases Page has a new Empty Trash button in the upper right navigation.

When clicking on the button, users will receive a warning including the number of cases in the ‘Move to Trash’ folder.

Upon confirmation, an activity will be recorded for the case deletion and if users are opted-in, they will receive an email confirmation.

Attach PON to kit

To support CNV calling in targeted panel and exome cases, DRAGEN employs a panel of normals (PON) approach, using a set of matched normal samples to establish a baseline for CNV event detection.

A PON file contains absolute paths to 'target counts' files of individual matched normal samples. While PON file generation remains unchanged, with this release, customers and support teams can attach PONs to a kit using combined counts files instead of a manual workflow.

In your organization settings page, you will see a new dedicated PON management.

The PON table includes the Kit Name, Kit ID, GC Corrected Status, Human Reference, DRAGEN Version and the Maximum Interval Size.

The PON table is searchable by kit name and any PON in the table is downloadable in CSV format.

If an organization contains PONs that have not been migrated to the table view, a warning will be displayed.

Adding/deleting a PON

To add a PON users must select values for mandatory fields – kit, human reference and DRAGEN version. The kits displayed will include all of the available unique kits to the organization (common kits must be moved to the organization to add a PON).

Only one combined.counts.txt.gz file can be selected from any of the supported storages: AWS S3, BaseSpace, and ICA Storage.

The component will perform a validation to ensure the target interval size does not exceed 250 bp for DRAGEN versions up to 4.2, and 500 bp for versions 4.3 and up. The validation is only performed on the first 1000 rows of the file. GC correction status is inferred from the file header or value formats.

To delete a PON simply click the trash button and approve the confirmation message. A deletion of a PON will record an activity.

To migrate your PONs to this new table please submit a support request to [e-mail] or your bioinformatics support team.

Limitations:

Cases Page | Move to Trash and Empty Trash are not available for in-progress or issue reported cases.

Settings | Add PON to Kit | File browser BSSH integration does not support searching by file name.

Known Issues:

Settings | Add PON to Kit | File browser will extract the wrong file extension if there is a ‘.’ In the file name. This is a display issue, won’t affect validation.

Annotations & Quality Updates

For GRCh38, updated to the gnomAD SV 4.1

In version 37, we now support the latest release of gnomAD SV v4, which includes structural variant data: deletions (DEL), duplications (DUP), and insertions (INS) from 63,046 genome-sequenced unrelated samples.

Unlike the previous GRCh38 release which was a liftover mapping from GRCh37 (dbVAR_nstd166), this version is natively aligned to the GRCh38 human reference, offering improved annotation accuracy, enhanced genome coverage, fewer errors, and a larger sample size. Additionally, it includes homozygote and hemizygote counts, along with direct links to the gnomAD website for detailed variant information. Since gnomAD SV v4 is only available for GRCh38, Emedgene will continue using gnomAD SV v2.1 for the GRCh37 pipeline to avoid errors and inconsistencies associated with liftover mapping.

SpliceAI version update with indels support and distance data

We provide updated annotations for variants with predicted effects on splicing, as described in Jaganathan et al., Cell, 2019. In this version, we updated SpliceAI pre-calculated files to SpliceAI v1.3 for SNVs and now also for indels. This update covers all possible single-nucleotide substitutions (SNVs), 1-base insertions, and 1–4 base deletions. We also added coverage for all gnomAD indels using an additional pre-calculated file (direct communication). The variant annotations are masked (weak values are converted to 0), and calculated using a 50 bp window and are available for both GRCh37 and GRCh38 reference genomes.

In addition to SpliceAI delta scores, which represent the probability that a variant affects splicing, we provide the distance to the position with the largest change in splicing probability. Negative/positive values indicate positions upstream/downstream of the variant based on genomic coordinates.

For STRs, added allele distribution in the quality tab

We are now including an allele distribution table which includes the ‘In repeat’, ‘Flanking’ and ‘Spanning’ information provided in the repeats VCF.

Limitations

For multi-allelic STR variants, the ref will be marked as N/A in the allele distribution table.

Voice of Customer

20% of each Emedgene release is allocated to customer feature requests. Sharp-eyed users will notice a new link to Feature Requests under the ? and Help Center link. We will launch a customer-facing feature request system with voting over the coming weeks.

New protein domain visualization track

Immediately under the RefSeq track we have added a Protein domain visualization track, using data from Uniprot GRCh38 with a liftover to GRCh37. Clicking a domain will display Name, start, end, ID and link out to UniProt.

Customize disease name for reporting

Emedgene now supports editing the selected disease associated with a gene on the Variant Page, and also customizing the disease name for reporting purposes.

When selecting a new disease from the associated gene disease connection list, the evidence graph will also be modified for the variant.

If none of the associated diseases are appropriate for reporting/exporting purposes, a user can click on the plus button within the component and create a new custom disease name. This disease name can be populated to the report, but will only be stored in the case. Emedgene Curate does not yet support custom gene-disease connections or custom disease names.

Emedgene Curate now displays number of variants and genes, including when searching.

For variants, the count displays the number of total filtered variants from the native curate organization and the number of filtered variant interpretations from the network.

Storage integration with Google Cloud

Emedgene now supports Google Cloud in our no-data-movement storage integrations, which include ICA, BSSH, Amazon S3, Azure Data Lake, Azure Blob, FTP and SFTP.

Read more about configuring Google Cloud storage in your organization.

Added reporting fonts, including for Japanese and Thai

More font reporting options have been added to our reporting server, for lab customization. Reporting content can also be added in Japanase and Thai.

Updated and enhanced Swagger for Emedgene Analyze

We’ve made it easier than ever to integrate into Emedgene APIs, to streamline and automate case accessioning, export and more.

• Updated swagger https://[org_name].emg.illumina.com/api/apidoc/swagger#/

• Updated introductory API integrations article

• Updated advanced API integrations article

• Updated webhooks integrations article

Enhancement

Added the DRAGEN mapping metrics CSV file to the outputs folder.

Known Issues:

Reanalysis | Custom disease is not saved when a case is reanalyzed.

Limitations

• Login | Emedgene does not support accents in User Names, despite support for these in IAM console. Users will not be able to login to the software.

• Add New Case | No validation that input files are uncorrupted, case will be created and fail.

• Add New Case | Selecting a disease should automatically suggest phenotypes, however, some diseases available for selection are from sources without phenotypes, and in that case, no phenotypes will be suggested.

• Add New Case | Adding metrics.tar.gz files is not supported from BSSH.

• Add New Case | API/Batch/UI discrepancies:

  • Cannot add phenotypes for unaffected parent in batch upload.

  • Cannot use the same gVCF file for multiple samples from the UI

  • No validation for sample name in array JSON from batch upload/API

• Cases Page | Move to Trash and Empty Trash are not available for in-progress or issue reported cases.

• Candidates, Variant Page, Curate | Evidence graph & ACMG automation will not be calculated for CNVs over 20MB. They will not have a gene related disease card in Curate.

• Lab Tab | Peddy contamination calculations may be inaccurate for panels due to small number of variants.

• Analysis Tools | Manually Added Variants | STRs | Format is not aligned with format of STRs on the software, e.g. missing variant length.

• Analysis Tools | Filters | DRAGEN SV caller contain a discrepancy between the VCF filter column and format field.

• Analysis Tools | Presets | Preset filters v1 schema is deprecated, please upgrade to V2 prior to moving to this version.

• Candidates, Variant Page | After editing the evidence graph, phenotypic match strength indications are missing from the sidecar and variant page.

• Variant Page | Max AF in the analysis tools and export is across population DBs; the gnomAD card displays a different Max AF, referring only to gnomAD data.

• Curate | Discrepancy between Analyze and Curate HGVS parser may be experienced.

• Network | GRCh37<-->GRCh38 Liftover not available for older components of Network infrastructure, as a result, [Variant Page | Clinical Significance | Networks Classified] may remain erroneously empty while [Variant page | Related cases section] shows relevant information. Same gap for manually classified variants.

• Webhooks | Cannot be trigger on internal software statuses such as ‘In Progress’ ‘Reanalysis’.

• Reporting | PMIDs will only work if there is an author on link, no support for books.

• Export to excel is limited to 32KB per cell, which may prevent exports with very large CNVs.

• Organization Settings | BED upload | Validation on the UI component does not check the following. No validation at all for API uploads.

  • All lines in the BED must contain the same number of columns.

  • No duplicate lines.

  • No trailing whitespaces.

• Settings | Add PON to Kit | File browser BSSH integration does not support searching by file name.

Fixed Issues

• Add New Case | Storage | Fixed issues with BSSH storage integration that 1) allows using human readable paths in batch upload, 2) Integration only passes QCPassed datasets.

• Add New Case | Fixed a limitation where ICA storage integration did not show linked files from BSSH managed projects.

• Add New Case | Fixed a limitation where targeted.json files were not supported in the batch upload.

• Edit Case | Fixed an issue where last button in flow always revalidated input data.

• Edit Case | Fixed issue preventing some changes in Region of Interest BED in reanalysis.

• Pipeline | Transcript selection logic update to fix an issue where sometimes fusion genes are prioritized.

• Analysis Tools | Fixed discrepancy between simple and advanced filter modes for quality and polymorphism filter, where switching would return a different number due to some basic filtering in advanced mode that was on by default.

• Analysis Tools | Default sort by AI rank has a secondary sort by genomic coordinates.

• Variant Page | Summary | Fixed an issue where mtDNA variants displayed max AF from gnomAD did not utilize all sub populations, resulting in inaccuracy.

• Variant Page | Summary | Fixed an issue occurring when ACMG tags were updated by users, the summary component is erroneously not updated.

• Variant Page | Clinical Significance | Fixed an issue DANN score showing as 0 on GRCh38 variants. DANN data is only available on GRCh37, and should not be visible for GRCh38 variants.

• Variant Page | Visualization | Fixed an issue where the IGV component performed a mean calculation when zooming out, typically around 3Mbp, which affected BAF and BigWig files visualization.

• Variant Page | Visualization | Fixed an issue where the error "cannot read properties of undefined” appeared intermittently due to IGV component limitation.

• Variant Page | Related Cases | Fixed an issue for organizations on Illumina clouds, workgroup alias is now shown instead of workgroup ID.

• Variant Page | Evidence | Fixed an issue where ACMG notes weren’t saved if tag was changed.

• Variant Page | Evidence | For finalized cases, fixed an issue where ACMG notes were not visible.

• Variant Page | Fixed an issue where for chrY haploid males, HOM zygosity displayed instead of HEMI.

• Lab Tab | Fixed an issue when sample gender unknown, sex validation will never fail, and the predicted sex will be displayed if available. Previously results were confusing as default gender in Emedgene was Female, so predicted Male will show up as failed.

• Versions Tab | After a reanalysis, some input files may not appear in versions tab.

• Report/Export | Fixed an issue where some customers couldn’t report on insufficient coverage regions.

• Curate | Fixed an issue where batch upload performed unnecessary UI validation, only a backend validation is performed now.

• Curate | Removed a limitation where only one amino acid was supported in the protein alt.

• Activity | Fixed an issue where interpretation text activity was not recorded correctly when user lacked some roles.

• General | Enabled right click open case in a new tab functionality from cases page.

Known Issues

• Add New Case | API | When sending due date please use UTC time, customer time zone is not taken into account with API, only through the UI.

• Add New Case | Replacing a sample in the UI will not change the visible sample name.

• Edit Case | Reanalysis | If HPO terms were updated between analyses, the reanalysis will not automatically map previous HPO terms to new ones.

• Edit Case | Reanalysis | Custom disease is not saved when a case is reanalyzed.

• Pipeline | A very low frequency pipeline timeouts can impact variant merge logic so that it doesn’t follow documented logic by VCF source. Expected prioritization: 1. "TARGETED" 2. "STAR_ALLELE" 3. "STR_REPEAT_EXPANSION" 4. "MRJD" 5. "FORCED_GENOTYPING" 6. "SMALL_VARIANT" 7. "CNV_READ_DEPTH" 8. "SV_SPLIT_END" 9. "UNKNOWN". Hotfix planned.

• Cases Page | Illumina Clouds | Users that have been removed from workgroups in IAM can still be added as participants to a case. They will not have access to the software, and there is no security/access risk.

• Cases Page | Reupload fails for JSON files.

• Lab Tab | Insufficient coverage export will not work via UI or API if an included gene does not have a start or end position in NCBI.

• Lab Tab | When a gene is removed from the knowledge graph, no coverage will be shown, until gene is removed from gene list.

• Lab Tab | Open in IGV desktop only works if case has been previously linked to IGV desktop from the analysis tools.

• Analysis Tools | Filters | Filtering on prediction scores will intermittently not work for panel cases. Hotfix planned.

• Analysis Tools | Intermittent issues using variant type filters in combination with variant effects, will be resolved with a refresh.

• Analysis Tools | Search | Searching for ‘chromosome: position ref > alt’ is not yet implemented for CNVs.

• Analysis Tools | Filters | Not all variant effects are available in advanced mode, full documentation here.

• Analysis Tools | Compound het filters | Don’t ignore samples that are set to ignore in the pipeline.

• Analysis Tools | ‘Last’ button on pagination does not work.

• Candidates Page | Compound het SNV-CNV variants will not display the automated CNV classification. Workaround – view variants from analysis table.

• Variant Page | Open in Curate for CNVs will be inaccurate due to not taking into account the correct variant overlap.

• Variant Page | Clinical Significance | For reanalyzed cases, network classified variants may appear as N/A for cases on GRCh38.

• Variant Page | Visualization | Simple/Advanced selectors will not work for locally uploaded BAM files.

• Variant Page | Visualizations | Curate link isn’t working for Curate track variants.

• Variant Page | Population Statistics does not display mtDNA organization DBs even when the case is correctly annotated with the data.

• Variant Page | Related Cases | Not working as expected for SV insertions

• Variant Page | ACMG Automation | Reclassify is only available for cases that were run with pipeline v37.0, reclassify button might be visible for cases not eligble.

• Variant Page | ACMG Automation | Evidence text might not be accurate when new no double dipping logic is enabled.

• Variant Page | ACMG Automation | When manually changing a tag status from inactive to active and back again, tag status might be incorrect.

• Variant Page | Load to desktop IGV not working for ClinVar SV file.

• Curate | Searching for a variant causes the related cases to disappear even when search is removed. Work around is to refresh.

• Activity | Editing interpretation paragraph yields an erroneous activity labeled reanalysis.

• Organization Settings | API Gene Lists | Does not support NCBI only export/import. This is supported from the UI.

• Organization Settings | Set mandatory fields - does not work from the UI. Please contact support if you’d like to configure these fields for your account.

• Settings | Add PON to Kit | File browser will extract the wrong file extension if there is a ‘.’ In the file name. This is a display issue, won’t affect validation.

• Dashboard | Diagnostic Yield includes Uncertain as Resolved.