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Advanced variant cl...
Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data
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- Singer-Berk, Moriel (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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- Gudmundsson, Sanna (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Genteknologi,Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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- Baxter, Samantha (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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- Seaby, Eleanor G. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Genomic Informatics Group, University Hospital Southampton, Southampton, UK
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- England, Eleina (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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- Wood, Jordan C. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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- Son, Rachel G. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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- Watts, Nicholas A. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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- Karczewski, Konrad J. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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- Harrison, Steven M. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ambry Genetics, Aliso Viejo, CA, USA
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- MacArthur, Daniel G. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia
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- Rehm, Heidi L. (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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- O'Donnell-Luria, Anne (författare)
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine & Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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(creator_code:org_t)
- Elsevier BV, 2023
- 2023
- Engelska.
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 110:9, s. 1496-1508
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines’ PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Nyckelord
- gnomAD
- pLoF
- population data
- predicted loss-of-function variants
- PVS1
- variant classification
- variant interpretation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Singer-Berk, Mor ...
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Gudmundsson, San ...
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Baxter, Samantha
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Seaby, Eleanor G ...
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England, Eleina
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Wood, Jordan C.
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Son, Rachel G.
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Watts, Nicholas ...
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Karczewski, Konr ...
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Harrison, Steven ...
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MacArthur, Danie ...
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Rehm, Heidi L.
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O'Donnell-Luria, ...
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