Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.

ABSTRACT:

Background

One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint". Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes.

Methods

We aim to identify missense variants that are significantly depleted in the general human population. Gi

SUBMITTER: Zhang X 

PROVIDER: S-EPMC11238507 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature