| Title: | FUSE: Improving the estimation and imputation of variant impacts in functional screening |
| Journal: | Cell Genomics |
| Published: | 1 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39389016/ |
| DOI: | https://doi.org/10.1016/j.xgen.2024.100667 |
Publication 13301
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Abstract
Deep mutational scanning enables high-throughput functional assessment of genetic variants. While phenotypic measurements from screening assays generally align with clinical outcomes, experimental noise may affect the accuracy of individual variant estimates. We developed the FUSE (functional substitution estimation) pipeline, which leverages measurements collectively within screening assays to improve the estimation of variant impacts. Drawing data from 115 published functional assays, FUSE assesses the mean functional effect per amino acid position and makes estimates for individual allelic variants. It enhances the correlation of variant functional effects from different assay platforms and increases the classification accuracy of missense variants in ClinVar across 29 genes (area under the receiver operating characteristic [ROC] curve [AUC] from 0.83 to 0.90). In UK Biobank patients with rare missense variants in BRCA1, LDLR, or TP53, FUSE improves the classification accuracy of associated phenotypes. FUSE can also impute variant effects for substitutions not experimentally screened. This approach improves accuracy and broadens the utility of data from functional screening.</p>
7 Keywords
- BRCA1 Protein
- Genetic Variation
- Humans
- Mutation, Missense
- Phenotype
- Receptors, LDL
- Tumor Suppressor Protein p53
6 Authors
- Tian Yu
- James D Fife
- Vineel Bhat
- Ivan Adzhubey
- Richard Sherwood
- Christopher A Cassa
1 Application
| Application ID | Title |
|---|---|
| 41250 | Prioritizing Mendelian variants using GWAS and exome sequencing data |
Enabling scientific discoveries that improve human health