gnomADsup1

gnomADsup1 annotates genetic variants with transcript expression-aware metrics, using the proportion expressed across transcripts (PEAT) and GTEx expression data to refine interpretation of coding and predicted loss-of-function (pLoF) variants in dosage-sensitive (haploinsufficient) genes.

Key Features:

• Alternative Splicing Consideration: Leverages alternative splicing information to account for exons expressed at varying levels across different cell types.
• Proportion Expressed Across Transcripts (PEAT) Metric: Introduces the PEAT metric to quantify isoform expression and to differentiate exons by evolutionary conservation and functional importance.
• Data Integration from GTEx Project: Utilizes expression data from 11,706 tissue samples in the Genotype Tissue Expression (GTEx) project to assess exon and isoform expression across diverse tissues.
• Selective Filtering of Variants: Applies expression-based annotation to filter out 22.8% of falsely annotated pLoF variants in haploinsufficient disease genes while preserving over 96% of high-confidence pathogenic variants.
• Application to Clinical Genetics: Applied to de novo variants in autism spectrum disorder, intellectual disability, and developmental disorders, finding that pLoF variants in weakly expressed regions have effect sizes similar to synonymous variants while pLoF variants in highly expressed exons are enriched among cases.

Scientific Applications:

• Genetic Diagnosis: Improves interpretation of rare disease variants by incorporating exon and isoform expression into pathogenicity assessment.
• Rare Variant Burden Analysis: Assists analysis of rare variant burden in complex disorders by stratifying variants by exon/isoform expression.
• Variant Curation and Prioritization: Supports curation and prioritization of variants for recall-by-genotype studies using expression-aware annotations.

Methodology:

Calculates the PEAT metric across multiple tissue types using GTEx expression data and applies expression-based annotation to variant files using isoform expression datasets.