Biology subjects

Stenton, S. L.

Publications and source records attributed to Stenton, S. L..

3 recordsLinked to original sources

bioRxiv2024

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria

PurposeWe previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong. A new generation of tools using distinctive approaches have since been released, and these methods must be independently calibrated for clinical application. MethodUsing our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by three new tools (AlphaMissense, ESM1b, VARITY) and calibrated scores meeting each evidence strength. Results All three tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, though sometimes for few variants. Compared to previously recommended tools, these yielded at best only modest improvements in the tradeoffs of evidence strength and false positive predictions. ConclusionAt calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

bioinformatics↗

bioRxiv2024

Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants (pLoF) in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. We identified explanations for the presumed lack of disease manifestation in 701 of the variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders rarely occur, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.

genomics↗

bioRxiv2023

Inferring compound heterozygosity from large-scale exome sequencing data

Recessive diseases arise when both the maternal and the paternal copies of a gene are impacted by a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants in a gene for a given disorder, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in trans) rather than on the same copy (i.e. in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase can be determined by transmission, our approach estimates phase with 95.7% accuracy and remains accurate even for very rare variants (allele frequency < 1x10-4). We also correctly phase 95.9% of variant pairs in a set of 293 patients with Mendelian conditions carrying presumed causal compound heterozygous variants. We provide a public resource of phasing estimates from gnomAD, including phasing estimates for coding variants across the genome and counts per gene of rare variants in trans, that can aid interpretation of rare co-occurring variants in the context of recessive disease.

genomics↗