Clinical Significance section

The Clinical Significance section summarizes essential variant-level and gene-level information and indicates the gene's associated diseases.

This tab is comprised of five different blocks:

1. Variant Info

1. Variant type,

2. Main effect,

3. Zygosity in each sequenced family member,

4. Gene symbol and HGVS descriptions on coding DNA and protein levels. The transcript is marked:

   • with a tick - if it is canonical,

   • with a Curate logo - if it has been selected in your Curate database.

   

   You may change the reference transcript by selecting one from the dropdown menu, or adding one not listed. For certain variants, such as upstream or downstream gene variants, HGVS descriptions may not be available. In these cases, you have the option to manually input coding change information. The notation should adhere to the format: GENE,NM_123456:c.-123N>N (no spaces are allowed). Once added, this information becomes available for the report.\

1. Exon number and the total number of exons in the transcript chosen,

2. Links to resources, such as UCSC genome browser, GeneCards, PubMed, WikiGenes,

3. dbSNP ID and link (Note: SNV/Indel variants only),

4. SV Type: DEL/DUP (Note: CNVs only),

5. SV Length (Note: CNVs only),

6. Link to DECIPHER (Note: CNVs only).

7. ISCN (Note: CNVs only),

8. Cytoband

2. In silico Predictions

Standalone scores for Pathogenicity (Missense) Prediction, Conservation, and Splicing Prediction. These are the summarized indicators computed by our proprietary algorithm based on the in silico prediction tools' output. Click on the dropdown icon next to the score to see the individual scores.

Currently available in silico predictions per variant type:

	SNV	Indel	mtDNA (SNV/indel)
Pathogenicity (Missense) Prediction	+ Polyphen2 HDIV Polyphen2 HVAR SIFT MutationTaster LRT DANN REVEL PrimateAI-3D (34.0+)	-	+ APOGEE MitoTIP
Conservation	+ SiPhy 29 Mammals GERP RS phastCons 100 vertebrate	+ GERP RS	-
Splicing Prediction	+ dbscSNV-RF dbscSNV-Ada SpliceAI DS AG SpliceAI DS AL SpliceAI DS DG SpliceAI DS DL	-	-

Note: variants of types CNV, SV and STR are not annotated with in silico predictions.

3. Gene Metrics

from ExAC and gnomAD that resemble clinically relevant gene properties:

1. p(LoF intolerant)

pLI = p(LoF intolerant) is a probability of being loss-of-function intolerant to heterozygous and homozygous LoF variants.

Scale:

• 🔴 pLI ≥ 0.9: extremely LoF intolerant,

• 🟠 pLI > 0.1 & < 0.9: intermediate value,

• 🟢 pLI ≤ 0.1: LoF tolerant.

2. Z missense

The Z missense score indicates intolerance to missense variants based on the deviation of observed missense variants versus the expected number.

Scale:

• 🔴 Z missense ≥ 3: missense intolerant,

• 🟠 Z missense > 2.5 & < 3: intermediate value,

• 🟢 Z missense ≤ 2.5: missense tolerant.

3. p(REC)

p(REC) is a probability of being intolerant to homozygous, but not heterozygous LoF.

Scale:

• 🔴 p(REC) ≥ 0.8: Hom LoF intolerant,

• 🟠 p(REC) > 0.2 & < 0.8: intermediate value,

• 🟢 p(REC) ≤ 0.2: Hom LoF tolerant.

4. RVIS ratio

RVIS = Residual Variation Intolerance Score is indicative of a gene's intolerance to functional variation based on comparing the overall number of observed variants in a gene to the observed common functional variants.

Scale:

• 🔴 RVIS ≤ 30: functional variation intolerant,

• 🟠 RVIS > 30 & < 50: intermediate value,

• 🟢 RVIS ≥ 50: functional variation tolerant.

5. pLoF o/e

O/E Score is the ratio of the observed/expected number of LoF variants. It is a continuous measure of gene tolerance to LoF variation that incorporates a 90% confidence interval. The closer the O/E is to zero, the more likely the gene is LoF-constrained. If a hard threshold is needed for the interpretation of Mendelian disease cases, use the upper bound of the O/E confidence interval < 0.35.

Note: Gene Metrics are not available for CNVs or mtDNA variants.

4. Gene's related diseases

as reported in OMIM, ORPHANET, CGD, ClinVar, and academic papers included in the Emedgene's knowledge graph. Each of the entries is provided with an inheritance mode icon and a link to the source.

5. Clinical significance

highlights previous pathogenicity classifications of the variant under review:

• Manually Classified indicates if the variant has been previously classified in any of the organization's cases by any user.

• Networks Classified indicates if the variant has been previously classified by the partnering organizations in your network.

Caution: Please be aware that as of 32.0 there might be instances where the Variant page > Clinical significance > Networks classified section appears erroneously empty. However, you can still rely on the Variant page > Related cases, which will continue to display relevant information as intended. Please utilize the Variant page > Related cases section while the fix is being implemented.

• Curate indicates if the variant has been previously classified in your Curate variant database.

• ClinVar provides a list of ClinVar submissions for the selected variant.

• ClinGen Regions (only for CNVs) indicates whether a variant overlaps the established dosage-sensitive region defined by ClinGen.

• Custom database shows a variant class from the variant database(s) curated by your organization. We can easily implement an organization's curated database of classified SNV or CNV variants to facilitate the case review.

• MITOMAP shows a variant's status in MITOMAP. By clicking on the MITOMAP interactive link, you will be taken to MITOMAP: Reported Mitochondrial DNA Base Substitution Diseases: Coding and Control Region Point Mutations.