Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels
dc.contributor.author | Cannon, S | |
dc.contributor.author | Williams, M | |
dc.contributor.author | Gunning, AC | |
dc.contributor.author | Wright, CF | |
dc.date.accessioned | 2023-03-03T08:26:38Z | |
dc.date.issued | 2023-02-28 | |
dc.date.updated | 2023-03-03T08:01:06Z | |
dc.description.abstract | Background: The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. Methods: We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1–5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP. Results: Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81–0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools’ training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64–0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset). Conclusions: Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools. | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.description.sponsorship | Health Innovation Challenge Fund | en_GB |
dc.description.sponsorship | Wellcome Trust Sanger Institute | en_GB |
dc.identifier.citation | Vol. 16 (1), article 36 | en_GB |
dc.identifier.doi | https://doi.org/10.1186/s12920-023-01454-6 | |
dc.identifier.grantnumber | MR/T00200X/1 | en_GB |
dc.identifier.grantnumber | HICF-1009-003 | en_GB |
dc.identifier.grantnumber | WT098051 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/132591 | |
dc.identifier | ORCID: 0000-0003-2958-5076 (Wright, CF) | |
dc.language.iso | en | en_GB |
dc.publisher | BMC | en_GB |
dc.rights | © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. | en_GB |
dc.subject | Pathogenicity | en_GB |
dc.subject | In-frame indels | en_GB |
dc.subject | Variant interpretation | en_GB |
dc.subject | Pathogenicity prediction | en_GB |
dc.title | Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2023-03-03T08:26:38Z | |
exeter.article-number | 36 | |
dc.description | This is the final version. Available from BMC via the DOI in this record. | en_GB |
dc.description | All variants in the final dataset are included in Additional file 2. The publicly available variant datasets are available from gnomAD [22] or ClinVar [10]. Genomic datasets from the DDD Study are available under managed access for research into developmental disorders via the European Genome-phenome Archive (EGAS00001000775). Individual pathogenic/likely pathogenic variants are openly accessible with phenotypes via DECIPHER [38]. | en_GB |
dc.identifier.eissn | 1755-8794 | |
dc.identifier.journal | BMC Medical Genomics | en_GB |
dc.relation.ispartof | BMC Medical Genomics, 16(1) | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2023-02-09 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2023-02-09 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2023-03-03T08:19:23Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2023-03-03T08:28:56Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2023-02-28 |
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Except where otherwise noted, this item's licence is described as © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.