Exome

Sociology

Exome sequencing

Genomics

Population

Biology

1000 Genomes Project

Gene

Genotype

Demography

Genome

Single-nucleotide polymorphism

Human genome

Whole genome sequencing

Human genetics

Mutation

Computational biology

Missense mutation

Genetics

Nature Genetics

Millions of human genomes and exomes have been sequenced, but their clinical applications remain limited due to the difficulty of distinguishing disease-causing mutations from benign genetic variation. Here we demonstrate that common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to be systematically identified by the process of elimination. Using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy and enables the discovery of 14 new candidate genes in intellectual disability at genome-wide significance. Cataloging common variation from additional primate species would improve interpretation for millions of variants of uncertain significance, further advancing the clinical utility of human genome sequencing. Using common variants in six non-human primate species, the authors train a deep neural network that identifies pathogenic mutations in patients with rare disease with 88% accuracy and enables the discovery of 14 new candidate genes in intellectual disability.

Predicting the clinical impact of human mutation with deep neural networks