A deep catalog of protein-coding variation in 985,830 individuals.

Area of Science:

• Genomics
• Human Genetics
• Bioinformatics

Background:

• Rare coding variants offer crucial biological insights but require large sample sizes for identification.
• Existing catalogs lack comprehensive data on rare variants across diverse ancestries.

Approach:

• Exome sequencing of 985,830 individuals from diverse ancestries to create a large-scale human coding variation catalog.
• Analysis of missense and predicted loss-of-function (pLOF) variants, including novel and rare homozygous pLOF.
• Integration of data to estimate selection, identify intolerant genes, and interpret variants of unknown significance.

Key Points:

• Catalog includes ~10.5 million missense and 1.1 million pLOF variants, with a high proportion of novel and rare variants.
• Identified homozygous pLOF variants in 4,874 genes, with 1,838 genes documented for the first time.
• Revealed insights into loss-of-function intolerance, missense variation depletion, cryptic splice site interpretation, and actionable variants.

Conclusions:

• The generated catalog is the largest to date, significantly advancing the study of rare coding variants.
• This resource aids in understanding gene function, disease mechanisms, and advancing precision medicine.
• Public accessibility via a variant allele frequency browser ensures broad utility for the scientific community.