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Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification

AlphaMissense is a recently developed method that is designed to classify missense variants into pathogenic, benign, or ambiguous categories across the entire human proteome. Asparagine Synthetase Deficiency (ASNSD) is a developmental disorder associated with severe symptoms, including congenital mi...

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Autores principales: Staklinski, Stephen J., Scheben, Armin, Siepel, Adam, Kilberg, Michael S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634951/
https://www.ncbi.nlm.nih.gov/pubmed/37961642
http://dx.doi.org/10.1101/2023.10.30.564808
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author Staklinski, Stephen J.
Scheben, Armin
Siepel, Adam
Kilberg, Michael S.
author_facet Staklinski, Stephen J.
Scheben, Armin
Siepel, Adam
Kilberg, Michael S.
author_sort Staklinski, Stephen J.
collection PubMed
description AlphaMissense is a recently developed method that is designed to classify missense variants into pathogenic, benign, or ambiguous categories across the entire human proteome. Asparagine Synthetase Deficiency (ASNSD) is a developmental disorder associated with severe symptoms, including congenital microcephaly, seizures, and premature death. Diagnosing ASNSD relies on identifying mutations in the asparagine synthetase (ASNS) gene through DNA sequencing and determining whether these variants are pathogenic or benign. Pathogenic ASNS variants are predicted to disrupt the protein’s structure and/or function, leading to asparagine depletion within cells and inhibition of cell growth. AlphaMissense offers a promising solution for the rapid classification of ASNS variants established by DNA sequencing and provides a community resource of pathogenicity scores and classifications for newly diagnosed ASNSD patients. Here, we assessed AlphaMissense’s utility in ASNSD by benchmarking it against known critical residues in ASNS and evaluating its performance against a list of previously reported ASNSD-associated variants. We also present a pipeline to calculate AlphaMissense scores for any protein in the UniProt database. AlphaMissense accurately attributed a high average pathogenicity score to known critical residues within the two ASNS active sites and the connecting intramolecular tunnel. The program successfully categorized 78.9% of known ASNSD-associated missense variants as pathogenic. The remaining variants were primarily labeled as ambiguous, with a smaller proportion classified as benign. This study underscores the potential role of AlphaMissense in classifying ASNS variants in suspected cases of ASNSD, potentially providing clarity to patients and their families grappling with ongoing diagnostic uncertainty.
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spelling pubmed-106349512023-11-13 Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification Staklinski, Stephen J. Scheben, Armin Siepel, Adam Kilberg, Michael S. bioRxiv Article AlphaMissense is a recently developed method that is designed to classify missense variants into pathogenic, benign, or ambiguous categories across the entire human proteome. Asparagine Synthetase Deficiency (ASNSD) is a developmental disorder associated with severe symptoms, including congenital microcephaly, seizures, and premature death. Diagnosing ASNSD relies on identifying mutations in the asparagine synthetase (ASNS) gene through DNA sequencing and determining whether these variants are pathogenic or benign. Pathogenic ASNS variants are predicted to disrupt the protein’s structure and/or function, leading to asparagine depletion within cells and inhibition of cell growth. AlphaMissense offers a promising solution for the rapid classification of ASNS variants established by DNA sequencing and provides a community resource of pathogenicity scores and classifications for newly diagnosed ASNSD patients. Here, we assessed AlphaMissense’s utility in ASNSD by benchmarking it against known critical residues in ASNS and evaluating its performance against a list of previously reported ASNSD-associated variants. We also present a pipeline to calculate AlphaMissense scores for any protein in the UniProt database. AlphaMissense accurately attributed a high average pathogenicity score to known critical residues within the two ASNS active sites and the connecting intramolecular tunnel. The program successfully categorized 78.9% of known ASNSD-associated missense variants as pathogenic. The remaining variants were primarily labeled as ambiguous, with a smaller proportion classified as benign. This study underscores the potential role of AlphaMissense in classifying ASNS variants in suspected cases of ASNSD, potentially providing clarity to patients and their families grappling with ongoing diagnostic uncertainty. Cold Spring Harbor Laboratory 2023-11-02 /pmc/articles/PMC10634951/ /pubmed/37961642 http://dx.doi.org/10.1101/2023.10.30.564808 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Staklinski, Stephen J.
Scheben, Armin
Siepel, Adam
Kilberg, Michael S.
Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title_full Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title_fullStr Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title_full_unstemmed Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title_short Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
title_sort utility of alphamissense predictions in asparagine synthetase deficiency variant classification
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634951/
https://www.ncbi.nlm.nih.gov/pubmed/37961642
http://dx.doi.org/10.1101/2023.10.30.564808
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