This track shows MPC v4.1.1 ("Missense deleteriousness Prediction by Constraint"), a machine-learning score that predicts which missense variants are likely to be deleterious. It was computed by the Broad Institute gnomAD team from the gnomAD v4.1.1 release of 730,947 exomes aligned to GRCh38/hg38. Scores are provided for every possible single-nucleotide -missense variant in 17,841 MANE Select or canonical protein-coding -transcripts that passed gnomAD QC, as well as for an additional 1,534 -transcripts that failed QC (the authors note that scores may be less -accurate in these 1,534 transcripts). +missense variant across 18,245 MANE Select or canonical protein-coding +transcripts.
Missense variants change a single amino acid in a protein and are a common source of variants of uncertain significance (VUS): about 90% of missense variants in ClinVar are VUS. MPC predicts which missense variants are likely deleterious by combining three lines of evidence: (i) regional missense constraint (how depleted the surrounding sub-genic region is of rare missense variation in the general population), (ii) the biochemical severity of the specific amino-acid substitution and additional protein-structure and homology information from PolyPhen-2, and (iii) cross-species conservation (phyloP). Higher scores indicate greater predicted deleteriousness.