ArticleAmerican journal of human genetics2023
Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data.
Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed.
- AAVC: An automated framework for high-accuracy ACMG-based variant classification.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Exome-wide association study of blood lipids in 1,158,017 individuals from diverse populations.Nature genetics · 2026Article
- Unifying the Communities of Early-Onset Glycogen Storage Disease Type IV and Adult Polyglucosan Body Disease Through a Genetic Prevalence Study ofJIMD reports · 2026Article
- Integrating 730,947 exome sequences with clinical literature improves gene discovery.medRxiv : the preprint server for health sciences · 2026Article
- EBF2 variant identified in a patient with atypical partial lipodystrophy causes adipose fibrosis and dysfunction.The Journal of clinical investigation · 2026Article
- Loss of function of the chromatin remodeling geneProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Regional nonsense constraint offers biological and clinical insights into genetic disease.Nature communications · 2026Article
- Genomic stop codon scanning reveals quantitative principles of nonsense-mediated mRNA decay.bioRxiv : the preprint server for biology · 2025Article
- Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks.American journal of human genetics · 2025Article
- Analysis and Interpretation of Somatic NMD-Escaping Variants in Oncogenes and Dual-Function Genes across Adult and Pediatric Cancer Cohorts.medRxiv : the preprint server for health sciences · 2025Article
- Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.Nature communications · 2025Article
- Article
- GREGoR: Accelerating Genomics for Rare Diseases.ArXiv · 2024Article
- An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration.Orphanet journal of rare diseases · 2024Article
- Bi-allelic PRRT2 variants may predispose to Self-limited Familial Infantile Epilepsy.European journal of human genetics : EJHG · 2024Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Improving estimates of loss-of-function constraint for short genes.Nature genetics · 2024Article
- Comparison of the ABC and ACMG systems for variant classification.European journal of human genetics : EJHG · 2024Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.bioRxiv : the preprint server for biology · 2024Article
- AutoGVP: a dockerized workflow integrating ClinVar and InterVar germline sequence variant classification.Bioinformatics (Oxford, England) · 2024Article
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Abstract
Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines' PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
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