aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants.

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Premature termination codons (PTCs) are common in pathogenic genomic variation.
• Nonsense-mediated mRNA decay (NMD) typically leads to loss-of-function from PTCs.
• Some PTCs escape NMD, causing dominant-negative or gain-of-function (DN/GOF) effects.

Purpose of the Study:

• To systematically identify human PTC-causing variants.
• To predict the susceptibility of PTC-containing transcripts to NMD.
• To investigate the role of DN/GOF alleles in human disease.

Main Methods:

• Development of aenmd, a user-friendly, self-contained software.
• Implementation of established and experimentally validated rules for NMD escape prediction.
• Application of aenmd to large-scale genomic databases (gnomAD, Clinvar, GWAS catalog).

Main Results:

• aenmd annotates PTC-containing transcript-variant pairs for NMD escape prediction.
• The software integrates seamlessly with existing analysis workflows and operates at scale.
• Prevalence of human PTC variants and potential DN/GOF variants was reported across major databases.

Conclusions:

• aenmd provides essential functionality for identifying PTC variants and predicting NMD escape.
• The findings contribute to understanding the contribution of DN/GOF alleles to human disease.
• The software is available as an R-package and a command-line interface.