ArticleGenetics in medicine : official journal of the American College of Medical Genetics2024
Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
- Predicting Oncogenic Mutants of Epidermal Growth Factor Receptor in Lung Cancer by Molecular Dynamics Simulation with Machine Learning.ACS omega · 2026Article
- Gene- and domain-aware calibration increases the clinical utility of variant effect predictors.Research square · 2026Article
- Calibration of in-frame indel variant effect predictors for clinical variant classification.bioRxiv : the preprint server for biology · 2026Article
- Ancestry-specific performance of variant effect predictors in clinical variant classification.bioRxiv : the preprint server for biology · 2026Article
- Integrative genomic and literature assessment of desmoglein 2-related arrhythmogenic cardiomyopathy with Italian cohort validation.Communications medicine · 2026Article
- De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders.Nature communications · 2026Article
- Reclassification of missense variant pathogenicity using ClinGen recommendations for recalibrated PP3/BP4 in silico predictor score thresholds.Genetics in medicine open · 2026Article
- acmgscaler: an R package and Colab for standardized gene-level variant effect score calibration within the ACMG/AMP framework.Bioinformatics (Oxford, England) · 2025Article
- Landscapes of missense variant impact for human superoxide dismutase 1.American journal of human genetics · 2025Article
- GDC: Integration of Multi-Omic and Phenotypic Resources to Unravel the Genetic Pathogenesis of Hearing Loss.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The global prevalence and genetic spectrum of primary carnitine deficiency.BMC genomic data · 2025Article
- Conserved missense variant pathogenicity and correlated phenotypes across paralogous genes.Genome biology · 2025Article
- Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Gene-based calibration of high-throughput functional assays for clinical variant classification.bioRxiv : the preprint server for biology · 2025Article
- Critical assessment of missense variant effect predictors on disease-relevant variant data.Human genetics · 2025Article
- Trio exome analysis is a valuable tool for genetic diagnosis of epilepsy in Mali.Genetics in medicine open · 2025Article
- Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.bioRxiv : the preprint server for biology · 2024Article
- Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes.American journal of human genetics · 2024Article
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13 authors.
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Abstract
purposeTo investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the ClinGen-calibrated PP3/BP4 computational recommendations.
methodsMissense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools that were able to reach PP3_Strong and BP4_Moderate evidence strengths (BayesDel, MutPred2, REVEL, and VEST4). The numbers of variants at each evidence strength were analyzed across disease-associated genes and genome-wide.
resultsFrom a median of 75.5 rare (≤1% allele frequency) missense variants in disease-associated genes per proband, a median of one reached PP3_Strong, 3-5 PP3_Moderate, and 3-5 PP3_Supporting. Most were allocated BP4 evidence (median 41-49 per proband) or were indeterminate (median 17.5-19 per proband). Extending the analysis to all protein-coding genes genome-wide, the number of variants reaching PP3_Strong score thresholds increased approximately 2.6-fold compared with disease-associated genes, with a median per proband of 1-3 PP3_Strong, 8-16 PP3_Moderate, and 10-17 PP3_Supporting.
conclusionA small number of variants per proband reached PP3_Strong and PP3_Moderate in 3424 disease-associated genes. Although not the intended use of the recommendations, this was also observed genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as pathogenic or likely pathogenic by ACMG/AMP rules.
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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 Socratic graph.