Comprehensive evaluation of AlphaMissense predictions by evidence quantification for variants of uncertain significance.

ABSTRACT: Accurate variant classification is critical for genetic diagnosis. Variants without clear classification, known as "variants of uncertain significance" (VUS), pose a significant diagnostic challenge. This study examines AlphaMissense performance in variant classification, specifically for VUS. A systematic comparison between AlphaMissense predictions and predictions based on curated evidence according to the ACMG/AMP classification guidelines was conducted for 5845 missense variants in 59 genes associated with representative Mendelian disorders. A framework for quantifying and modeling VUS pathogenicity was used to facilitate comparison. Manual reviewing classified 5845 variants as 4085 VUS, 1576 pathogenic/likely pathogenic, and 184 benign/likely benign. Pathogenicity predictions based on

SUBMITTER: Kurtovic-Kozaric A 

PROVIDER: S-EPMC11666499 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature