Appendix 3. Review Priority for Variants

Charlene Son-Rigby -

Fabric Genomics is focused on developing methodologies to accelerate identification of causative variants. The Review Priority field provides a visual prioritization of variants based on three color-coded data elements: ClinVar Classification, Allele Frequency and Effect.

Review Priority is represented visually using three colored circles. This field is sortable. Variants with more red circles will have higher review priority, and therefore be displayed higher in the sort order. 

Interpretation Priority is represented visually using three colored circles. 

 

Data Circle Position Definition
ClinVar Left Submission and classification status in ClinVar.  See ClinVar Classifications for explanations of ClinVar categories.
Allele Frequency Middle

Maximum allele frequency in 1K Genomes, ExAC and EVS reference databases

Effect Right Variant effect

 

Review Priority - Color Definition

This table outlines criteria for the color of each data element. Variants with more red circles will have higher review priority. 

Data  Circle Color Criteria
ClinVar Red A reference ClinVar record (RCV)* with at least one pathogenic or likely pathogenic classification that matches the allele
Yellow

An RCV with all VUS classifications; or

An RCV with any association classification where the allele does not already match Red or Green criteria. Association classifications are: confers sensitivity, drug response, protective and risk factor; or

A variant that does not match allele with any pathogenic/likely pathogenic class but does match at least one "Conflicting Interpretations of Pathogenicity"

Gray No classification provided in ClinVar or no exact allele match in ClinVar
Green An RCV that does not have any pathogenic/likely pathogenic or conflicting interpretations of pathogenicity classes but does have at least one benign or likely benign classification that matches the allele
Allele Frequency Red

<=1% or not present in any reference database

Yellow

>1% and <5%

Green

>=5%

Effect Red 

High likelihood of loss of function: 

  • Stop-gained
  • Stop-lost
  • Frame-shift deletion/insertion/substitution
  • Splice-site [AG/GT]
  • Transcript ablation
Yellow

Moderate likelihood of loss of function:

  • Missense
  • Inframe deletion/insertion
  • Splice region
  • Transcript amplification
Green

Low likelihood of effect on function:

  • Synonymous coding variants
  • 5’ and 3’ UTR variants
  • Variants in non-coding genes
  • Intronic variants excluding splice consensus
  • Intergenic variants including upstream and downstream
  • Regulatory region variant, ablation or amplification

   *A reference ClinVar record, or RCV, is the summary record for variant submissions for the same condition.

ClinVar Classifications

ClinVar uses standard terms and classifications for clinical significance, as follows:

Pathogenic (1) is any variant with exclusively pathogenic records.

Likely pathogenic (2) is any variant with exclusively likely pathogenic records or a combination of different records including at least one likely pathogenic or pathogenic record.  Two examples of combination records are:  

  • likely pathogenic and VUS
  • pathogenic and risk factor.

Uncertain Significance (3A) is a record that has exclusively uncertain significance records. 

Likely Benign (4) is a variant that has a combination of records including at least one likely benign or benign record.   Two examples of combination records are:  

  • benign and VUS
  • likely benign and VUS.

Benign (5) is any variant with exclusively benign records.

Associated (6) is a variant that has at least one of the following: "association", "confers sensitivity", "drug response", "protective", or "risk factor", with no other Pathogenic, Likely Pathogenic, Benign, or Likely Benign records (VUS records are acceptable).

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