Variant pathogenicity scoring and classification and uses thereof
AssigneeIllumina, Inc.
InventorsHong Gao, Kai-How Farh, Jeremy Francis McRae
Life of this patent
Estimating the term…
Abstract
Derivation and use of pathogenicity scores for gene variants are described herein. Applications, uses, and variations of the pathogenicity scoring process include, but are not limited to, the derivation and use of thresholds to characterize a variant as pathogenic or benign, the estimation of selection effects associated with a gene variant, the estimation of genetic disease prevalence using pathogenicity scores, and the recalibration of methods used to assess pathogenicity scores.
Claims21
A method for estimating a selection coefficient for a missense variant of a gene, the method comprising the steps of:
- calculating a depletion metric for the missense variant of the gene based on a pathogenicity percentile score of the missense variant and a relationship between the percentile pathogenicity scores and depletion metrics for the gene;
- and
- estimating the selection coefficient of the missense variant based on the depletion metric for the missense variant and a selection-depletion relationship derived for the gene.
A non-transitory computer-readable medium storing processor-executable instructions that, when executed by one or more processors, cause the one or more processors to perform steps comprising:
- calculating a depletion metric for a missense variant of a gene based on a pathogenicity percentile score of the missense variant and a relationship between the percentile pathogenicity scores and depletion metrics for the gene;
- and
- estimating a selection coefficient of the missense variant based on the depletion metric for the missense variant and a selection-depletion relationship derived for the gene.
A method for determining a selection coefficient associated with one or more mutations, the method comprising:
- determining a number of observed loss-of-function (LOF) mutations within an allele frequency dataset for the gene;
- calculating a depletion metric using the number of observed LOF mutations and an expected number of LOF mutations, wherein the depletion metric characterizes the proportion of LOF mutations removed by selection;
- and
- determining a selection coefficient for LOF mutations of the gene using the depletion metric.
Dependencies are inferred from the claim text.