2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Incorporating Regulatory Information Improves Interpretation of Noncoding Variants

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This document summarizes a study conducted by Lindsay Romo, Scott Findlay, and Christopher B. Burge, which explores the impact of regulatory elements on the interpretation of noncoding variants in the 3' untranslated region (3'UTR) of genes.<br /><br />The researchers found that noncoding variants in the 3'UTR region that are located within eCLIP peaks, RNA binding protein (RBP) motifs, and microRNA sites are more likely to affect gene expression compared to variants not in these elements. Additionally, variants that disrupt RBP motifs and microRNA sites are associated with altered gene expression.<br /><br />Furthermore, the study reveals that variants in RBP motifs are more likely to result in allele-specific RBP binding, suggesting functional impact. The researchers also found that variants in proximity to proximal alternative polyadenylation (APA) isoforms of genes with fewer isoforms have a greater impact on gene expression.<br /><br />The study also highlights that variants in the 3'UTR regulatory elements are much more likely to be classified as pathogenic in ClinVar compared to other 3'UTR variants. Some variants associated with phenotypes or gene expression in genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) analyses are classified as variants of unknown significance in ClinVar, suggesting that they may be pathogenic. The researchers propose that clinical sequencing should extend into 3'UTR regions to prioritize variants for functional studies.<br /><br />To aid in the interpretation of 3'UTR variants, the researchers developed a bioinformatic tool called CharVar, which characterizes any 3'UTR variant by its regulatory elements and predicts the likelihood of its impact on gene expression and phenotype.<br /><br />Overall, this study highlights the importance of considering regulatory information in the interpretation of noncoding variants in the 3'UTR region, providing valuable insights for clinical sequencing and functional studies.

Asset Subtitle

Presenting Author - Lindsay Romo, MD, PhD; Co-Author - Scott Findlay, PhD; Co-Author - Christopher Burge, PhD;

Meta Tag

Bioinformatics

Databases

Exome sequencing

Genetic Testing

Genome sequencing

Genotype-Phenotype Correlations

NextGen Sequencing

Population Genetics

Sequencing

Variant Detection

Co-Author Scott Findlay, PhD

Co-Author Christopher Burge, PhD

Presenting Author Lindsay Romo, MD, PhD

Keywords

regulatory elements

noncoding variants

3' untranslated region

gene expression

eCLIP peaks

RNA binding protein motifs

microRNA sites

allele-specific RBP binding

alternative polyadenylation isoforms

ClinVar