SORVA

SORVA assesses the significance of rare protein-altering variants by comparing their frequency and distribution within genes and protein domains to population control data for interpretation in Mendelian and complex disease studies.

Key Features:

• Variant Frequency Analysis: Calculates how often rare variants occur within specific genes under various filtering thresholds.
• Mutational Burden Calculation: Quantifies the number of individuals with rare variants in genic regions that map to protein domains to assess mutational burden.
• Statistical Significance Assessment: Computes the statistical significance of observing rare variants within a specified proportion of sequenced individuals.
• Gene Ranking Based on Variation Intolerance: Ranks genes by frequency counts to indicate intolerance to variation and compares these rankings with pLI scores from the ExAC dataset.

Scientific Applications:

• Mendelian disease studies: Applied to multi-family investigations of rare Mendelian genetic diseases to contextualize candidate variants against population variation.
• Complex disorder analyses: Used in large-scale studies of complex disorders, including autism spectrum disorder, to evaluate the contribution of rare variants.
• Candidate gene vetting: Provides quantitative, statistics-based evidence to support or refute candidate genes identified in sequencing studies.

Methodology:

Leverages genome-wide control data from 2,504 individuals in the 1000 Genomes Project; calculates variant frequencies under filtering thresholds; quantifies individuals with rare variants mapping to protein domains; computes statistical significance of observed variant proportions; ranks genes by frequency counts and compares rankings to ExAC pLI scores.