ArticleGenome medicine2017
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.
Article in Genome medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
105 citing papers in PubMed, 1 synthesis or guideline pooled it, 239 citations in OpenAlex.
- Evidence for penetrance in patients without a family history of disease: a systematic review.European journal of human genetics : EJHG · 2020Pooled it
- Article
- MutAnt: mutation annotation tool predicts deleteriousness of missense mutations and improves mutation calling from transcriptomics.Human genetics · 2025Article
- Genetic risk and clinical implications of BRCA1 and BRCA2 mutations in Turkish triple-negative breast cancer patients.Discover oncology · 2025Article
- Predisposition to prostate cancer and clinical implications in a real-life cohort.European journal of human genetics : EJHG · 2025Article
- Genetic insights into BRCA1/2 associated breast cancer in Türkiye: focus on early-onset and aggressive subtypes.Discover oncology · 2025Article
- Identification of intragenic variants in pediatric patients with intellectual disability in Peru.BMC medical genomics · 2025Article
- A Hitchhiker's Guide to long-read genomic analysis.Genome research · 2025Review
- Isolation and Characterization of the Adamantinomatous Craniopharyngioma Primary Cells with Cancer-Associated Fibroblast Features.Biomedicines · 2025Article
- Experience using conventional compared to ancestry-based population descriptors in clinical genomics laboratories.American journal of human genetics · 2025Review
- Structural and functional insights into α-actinin isoforms and their implications in cardiovascular disease.The Journal of general physiology · 2025Review
- The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance.Clinical genetics · 2025Article
- Troponin I - a comprehensive review of its function, structure, evolution, and role in muscle diseases.Animal cells and systems · 2025Review
- Interpreting Variants of Uncertain Significance in PCD: Abnormal Splicing Caused by a Missense Variant of DNAAF3.Molecular genetics & genomic medicine · 2025Article
- Exome sequencing reanalysis identifies a novel likely pathogenicFrontiers in medicine · 2025Article
- Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients.Bioinformatics and biology insights · 2025Article
- Interpreting the actionable clinical role of rare variants associated with short QT syndrome.Human genetics · 2024Article
- Actionable Variants of Unknown Significance in Inherited Arrhythmogenic Syndromes: A Further Step Forward in Genetic Diagnosis.Biomedicines · 2024Article
- Clinical Variant Reclassification in Hereditary Disease Genetic Testing.JAMA network open · 2024Article
- Comparison among different preclinical models derived from the same patient with a non-functional pancreatic neuroendocrine tumor.Human cell · 2024Article
45 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe frequency of a variant in the general population is a key criterion used in the clinical interpretation of sequence variants. With certain exceptions, such as founder mutations, the rarity of a variant is a prerequisite for pathogenicity. However, defining the threshold at which a variant should be considered "too common" is challenging and therefore diagnostic laboratories have typically set conservative allele frequency thresholds.
methodsRecent publications of large population sequencing data, such as the Exome Aggregation Consortium (ExAC) database, provide an opportunity to characterize with accuracy and precision the frequency distributions of very rare disease-causing alleles. Allele frequencies of pathogenic variants in ClinVar, as well as variants expected to be pathogenic through the nonsense-mediated decay (NMD) pathway, were analyzed to study the burden of pathogenic variants in 79 genes of clinical importance.
resultsOf 1364 BRCA1 and BRCA2 variants that are well characterized as pathogenic or that are expected to lead to NMD, 1350 variants had an allele frequency of less than 0.0025%. The remaining 14 variants were previously published founder mutations. Importantly, we observed no difference in the distributions of pathogenic variants expected to be lead to NMD compared to those that are not. Therefore, we expanded the analysis to examine the distributions of NMD expected variants in 77 additional genes. These 77 genes were selected to represent a broad set of clinical areas, modes of inheritance, and penetrance. Among these variants, most (97.3%) had an allele frequency of less than 0.01%. Furthermore, pathogenic variants with allele frequencies greater than 0.01% were well characterized in publications and included many founder mutations.
conclusionsThe observations made in this study suggest that, with certain caveats, a very low allele frequency threshold can be adopted to more accurately interpret sequence variants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.