ArticleAmerican journal of human genetics2022
Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 405 papers.
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
405 citing papers in PubMed.
- Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.European journal of human genetics : EJHG · 2026Article
- The population frequency of predicted pathogenic genetic variants in commonly affected CAKUT genes in the general population.Pediatric nephrology (Berlin, Germany) · 2026Article
- From Pathogenicity to Mechanism: A Variant Interpretation Framework for Monogenic Epilepsy.Clinical genetics · 2026Article
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Artificial Intelligence in Pediatric Cardiovascular Genetics: From Multimodal Diagnosis to Risk Prediction and Precision Therapeutics.International journal of molecular sciences · 2026Review
- Probabilistic mapping of sub-genic intolerance reveals functional and disease-critical protein regions.bioRxiv : the preprint server for biology · 2026Article
- Pathogenicity assessment of genetic variants in reproductive disorders.Journal of assisted reproduction and genetics · 2026Review
- Review
- Rapidly Progressive Infantile Dilated Cardiomyopathy in Long-Olsen-Distelmaier Syndrome Associated withGenes · 2026Article
- Article
- MNV-aware molecular characterization of a rare homozygous TTPA complex allele in ataxia with vitamin E deficiency.Molecular genetics and genomics : MGG · 2026Article
- Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.Acta neuropathologica · 2026Article
- Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.Human genetics · 2026Article
- Automated patch clamp data improve variant classification and penetrance stratification for SCN5A-Brugada syndrome.European heart journal · 2026Article
- Validation structures for sequence variants of uncertain significance in hereditary cancer.European journal of human genetics : EJHG · 2026Review
- Article
- Germline whole-exome sequencing identifies CTNND1 as a candidate gene for hereditary gastric cancer in a large Brazilian cohort.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2026Article
- Extending the global landscape of Bruck syndrome: Case series of Indonesian and Ukrainian patients with PLOD2 pathogenic variants and literature review.Bone reports · 2026Article
- The prevalence of protein misfolding as a mechanism for hereditary deafness.PLoS genetics · 2026Article
- Article
345 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
14 authors.
Funding
Abstract
Recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) for interpreting sequence variants specify the use of computational predictors as "supporting" level of evidence for pathogenicity or benignity using criteria PP3 and BP4, respectively. However, score intervals defined by tool developers, and ACMG/AMP recommendations that require the consensus of multiple predictors, lack quantitative support. Previously, we described a probabilistic framework that quantified the strengths of evidence (supporting, moderate, strong, very strong) within ACMG/AMP recommendations. We have extended this framework to computational predictors and introduce a new standard that converts a tool's scores to PP3 and BP4 evidence strengths. Our approach is based on estimating the local positive predictive value and can calibrate any computational tool or other continuous-scale evidence on any variant type. We estimate thresholds (score intervals) corresponding to each strength of evidence for pathogenicity and benignity for thirteen missense variant interpretation tools, using carefully assembled independent data sets. Most tools achieved supporting evidence level for both pathogenic and benign classification using newly established thresholds. Multiple tools reached score thresholds justifying moderate and several reached strong evidence levels. One tool reached very strong evidence level for benign classification on some variants. Based on these findings, we provide recommendations for evidence-based revisions of the PP3 and BP4 ACMG/AMP criteria using individual tools and future assessment of computational methods for clinical interpretation.
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.