An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance

Abriata LA, Palzkill T, Dal Peraro M (2015) How structural and physicochemical determinants shape sequence constraints in a functional enzyme. PLoS ONE 10:e0118684. https://doi.org/10.1371/journal.pone.0118684

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adhikari AN (2019) Gene-specific features enhance interpretation of mutational impact on acid α-glucosidase enzyme activity. Hum Mutat 40:1507–1518. https://doi.org/10.1002/humu.23846

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting Functional Effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 76. 7.20.1–7.20.41

Alirezaie N, Kernohan KD, Hartley T et al (2018) ClinPred: Prediction Tool to identify Disease-relevant Nonsynonymous single-nucleotide variants. Am J Hum Genet 103:474–483. https://doi.org/10.1016/j.ajhg.2018.08.005

Article  CAS  PubMed  PubMed Central  Google Scholar 

Alley EC, Khimulya G, Biswas S et al (2019) Unified rational protein engineering with sequence-based deep representation learning. Nat Methods 16:1315–1322. https://doi.org/10.1038/s41592-019-0598-1

Article  CAS  PubMed  PubMed Central  Google Scholar 

Anderson D, Lassmann T (2018) A phenotype centric benchmark of variant prioritisation tools. Npj Genom Med 3:5. https://doi.org/10.1038/s41525-018-0044-9

Article  CAS  PubMed  PubMed Central  Google Scholar 

Carter H, Douville C, Stenson PD et al (2013) Identifying mendelian disease genes with the variant Effect Scoring Tool. BMC Genomics 14:S3. https://doi.org/10.1186/1471-2164-14-S3-S3

Article  PubMed  PubMed Central  Google Scholar 

Cheng J, Novati G, Pan J et al (2023) Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381:eadg7492. https://doi.org/10.1126/science.adg7492

Article  CAS  PubMed  Google Scholar 

Clark WT, Yu GK, Aoyagi-Scharber M, LeBowitz JH (2018) Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence. PLoS ONE 13:e0200008. https://doi.org/10.1371/journal.pone.0200008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Clark WT, Kasak L, Bakolitsa C et al (2019) Assessment of predicted enzymatic activity of α-N-acetylglucosaminidase variants of unknown significance for CAGI 2016. Hum Mutat 40:1519–1529. https://doi.org/10.1002/humu.23875

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dehouck Y, Grosfils A, Folch B et al (2009) Fast and accurate predictions of protein stability changes upon mutations using statistical potentials and neural networks: PoPMuSiC-2.0. Bioinformatics 25:2537–2543. https://doi.org/10.1093/bioinformatics/btp445

Article  CAS  PubMed  Google Scholar 

Draelos RL, Ezekian JE, Zhuang F et al (2022) GENESIS: gene-specific machine learning models for variants of Uncertain significance found in Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome-Associated genes. Circ Arrhythm Electrophysiol 15:e010326. https://doi.org/10.1161/CIRCEP.121.010326

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fokkema IFAC, Kroon M, López Hernández JA et al (2021) The LOVD3 platform: efficient genome-wide sharing of genetic variants. Eur J Hum Genet 29:1796–1803. https://doi.org/10.1038/s41431-021-00959-x

Article  CAS  PubMed  PubMed Central  Google Scholar 

Frazer J, Notin P, Dias M et al (2021) Disease variant prediction with deep generative models of evolutionary data. Nature 599:91–95. https://doi.org/10.1038/s41586-021-04043-8

Article  CAS  PubMed  Google Scholar 

Greene H, Hug G, Schubert WK (1967) Arylsulfatase A in the urine and metachromatic leukodystrophy. J Pediatr 71:709–711. https://doi.org/10.1016/S0022-3476(67)80207-5

Article  CAS  PubMed  Google Scholar 

Hecht M, Bromberg Y, Rost B (2015) Better prediction of functional effects for sequence variants. BMC Genomics 16:S1. https://doi.org/10.1186/1471-2164-16-S8-S1

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hopf TA, Ingraham JB, Poelwijk FJ et al (2017) Mutation effects predicted from sequence co-variation. Nat Biotechnol 35:128–135. https://doi.org/10.1038/nbt.3769

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ioannidis NM, Rothstein JH, Pejaver V et al (2016) REVEL: an Ensemble Method for Predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885. https://doi.org/10.1016/j.ajhg.2016.08.016

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jain S, Bakolitsa C, Brenner SE et al (2024a) CAGI, the critical Assessment of Genome Interpretation, establishes progress and prospects for computational genetic variant interpretation methods. Genome Biol 25:53. https://doi.org/10.1186/s13059-023-03113-6

Article  Google Scholar 

Jain S, Trinidad M, Nguyen TB et al (2024b) Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A. 16.594558. https://doi.org/10.1101/2024.05.16.594558

Karamanos TK (2023) Chasing long-range evolutionary couplings in the AlphaFold era. Biopolymers 114:e23530. https://doi.org/10.1002/bip.23530

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kroos M, Hoogeveen-Westerveld M, Michelakakis H et al (2012) Update of the pompe disease mutation database with 60 novel GAA sequence variants and additional studies on the functional effect of 34 previously reported variants. Hum Mutat 33:1161–1165. https://doi.org/10.1002/humu.22108

Article  CAS  PubMed  Google Scholar 

Laimer J, Hofer H, Fritz M et al (2015) MAESTRO - multi agent stability prediction upon point mutations. BMC Bioinformatics 16:116. https://doi.org/10.1186/s12859-015-0548-6

Article  CAS  PubMed  PubMed Central  Google Scholar 

Landrum MJ, Lee JM, Benson M et al (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067. https://doi.org/10.1093/nar/gkx1153

Article  CAS  PubMed  Google Scholar 

Leferink NGH, Antonyuk SV, Houwman JA, Scrutton NS, Eady RR, Hasnain SS (2014) Impact of residues remote from the catalytic centre on enzyme catalysis of copper nitrite reductase. Nat Commun 5:4395 pmid:25022223

Article  CAS  PubMed  Google Scholar 

Li C, Zhi D, Wang K, Liu X (2022) MetaRNN: differentiating rare pathogenic and rare benign missense SNVs and InDels using deep learning. Genome Med 14:115. https://doi.org/10.1186/s13073-022-01120-z

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lin Z, Akin H, Rao R et al (2023) Evolutionary-scale prediction of atomic-level protein structure with a language model. Science 379:1123–1130. https://doi.org/10.1126/science.ade2574

Article  CAS  PubMed  Google Scholar 

Manfredi M, Savojardo C, Martelli PL, Casadio R (2022) E-SNPs&GO: embedding of protein sequence and function improves the annotation of human pathogenic variants. Bioinformatics 38:5168–5174. https://doi.org/10.1093/bioinformatics/btac678

Article  CAS  PubMed  PubMed Central  Google Scholar 

Meiyappan M, Concino MF, Norton AW (2015) Crystal structure of human alpha-n-acetylglucosaminidase. US Patent 20150031112A1, 29 Jan 2015

Comments (0)

No login
gif