Table 1.
Description and recommended pathogenicity thresholds for gene-based constraint metrics and intolerance scores for the assessment of multiple genes encompassed with large copy-number variants in patients.
| Algorithm | Description | Score | Threshold interpretation | Reference |
|---|---|---|---|---|
| pLI | Dichotomous metric that reflects the probability of loss of function intolerance based on predicted protein truncating variation: nonsense, splice acceptor and splice donor variation | 0 to 1 | pLI ≥ 0.9 = Extremely intolerant | (Samocha et al., 2014) (Lek et al., 2016) |
| Missense Z-score | Standard deviation of the # of observed rare (<1% MAF) missense SNP's from the mean of the predicted number of expected rare (<1% MAF) missense SNP's for a given gene. (Synonymous variants typically have Z-score close to 0 and o/e close to 1) | -5 to 5 | Z-score > 0 = More Intolerant Z-score < 0 = Less intolerant |
(Samocha et al., 2014) (Lek et al., 2016) |
| EvoTol percentile | Percentile ranking of a gene's evolutionary intolerance relative to other genes based on the number of damaging versus non-damaging variants in dbSNP. | Percentile (priority ranking) | Top 25th percentile = Intolerant Top 1 percentile = Most intolerant |
(Rackham et al., 2015) |
| RVIS percentile | Percentile ranking of a gene's intolerance to functional variation relative to other genes based on observed versus expected frequency of loss-of-function variants from the NHLBI-ESP6500 data set in ExAC (release 0.3). | Percentile (priority ranking) | Bottom 25th percentile = Intolerant (Genes are ranked from most to least intolerant) |
(Petrovski et al., 2013) |
| pcGERP percentile | Percentile estimate reflecting how conserved the protein-coding sequence of a gene relative to other genes | Percentile estimate | Lower percentile = More intolerance (increased conservation) (Genes are ranked from most to least intolerant) |
(Davydov et al., 2010) (Cooper et al., 2005) (Petrovski et al., 2015) |
Abbreviation: pLI, probability of being Loss-of-function Intolerant; EvoTol, Evolutionary Intolerance; RVIS, Residual Variation Intolerance Score; pcGERP, protein-coding Genomic Evolutionary Rate Profiling; MAF, minor allele frequency.