Regional missense constraint improves variant deleteriousness prediction

By Kaitlin E. Samocha, J. Kosmicki, Konrad J. Karczewski, Anne H. O'Donnell-Luria, Emma Pierce-Hoffman, Daniel G. MacArthur, Benjamin M. Neale, Mark J. Daly. 2017

358 citations recorded by the source corpus.

Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.

Subfields: Genetics, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Molecular Biology

Citations in the corpus

Variant interpretation using population databases: lessons from gnomAD (2021, background): “10 genes will have regions of missense constraint, often overlapping with functionally important domains (Samocha et al., 2017).”
Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders (2019, background): “In supplementary analyses, we did not find evidence of significant overrepresentation of genes related to pleiotropic SNPs identified here among previously defined genomic disorder regions or genes associated with neurodevelopmental disorders from rare variant studies (including ASD, intellectual di”
dbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs (2020, background): “…CADD_hg19 [16], ClinPred [17], DEOGEN2 [18], Eigen and Eigen PC [19], FATHMM-XF [20], GenoCanyon [21], LINSIGHT [22], LIST-S2 [23], M-CAP [24], MPC [25], MutPred [26], MVP [27], PrimateAI [28], REVEL [29], SIFT4G [30]), one score for loss of function prediction (ALoFT [31]), and three conservation…”
LIST-S2: taxonomy based sorting of deleterious missense mutations across species (2020, methodology): “0a (17) (namely: SIFT (1), SIFT4G (18), PROVEAN (2), phyloP (3) X 3, SiPhy (5), phastCons (6) X 3, GERP++ (4), Eigen (10), CADD (9), DANN (11), W158 Nucleic Acids Research, 2020, Vol. 48, Web Server issue PolyPhen-2 (8), FATHMM-MKL (19), PrimateAI (20), MutationTast (21), MutationAssessor (22), MPC ”