Lightway access to AlphaMissense data that demonstrates a balanced performance of this missense mutation predictor

Tordai, H.; Torres, O.; Csepi, M.; Padányi, R.; Lukács, G. L.; Hegedűs, T.

doi:10.1101/2023.10.30.564807

Cited by 4 publications

(4 citation statements)

References 39 publications

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“…Predictions of the pathogenic effects of missense variants were performed with a web-based version of the AlphaMissense database. 45 …”

Section: Methodsmentioning

confidence: 99%

Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes

Bittner,

Shi,

Zhao

et al. 2024

Ann Rheum Dis

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ObjectivesOsteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in three-dimensional (3D) space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel candidate effector genes for the disease.MethodsPrimary chondrocytes collected from 8 patients with knee osteoarthritis underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results and epigenomic data from primary knee osteoarthritis chondrocytes to identify variants involved in gene regulation via enhancer-promoter interactions.ResultsWe identified 345 genetic variants residing within chromatin loop anchors that are associated with 77 osteoarthritis GWAS signals. Ten of these variants reside directly in enhancer regions of 10 newly described active enhancer-promoter loops, identified with multiomics analysis of publicly available chromatin immunoprecipitation sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) data from primary knee chondrocyte cells, pointing to two new candidate effector genesSPRY4andPAPPA (pregnancy-associated plasma protein A)as well as further support for the geneSLC44A2known to be involved in osteoarthritis. For example, PAPPA is directly associated with the turnover of insulin-like growth factor 1 (IGF-1) proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes.ConclusionsWe have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D genomics with large-scale genetic association and epigenetic data, we identify novel candidate effector genes for osteoarthritis, which enhance our understanding of disease and can serve as putative high-value novel drug targets.

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“…Predictions of the pathogenic effects of missense variants were performed with a web-based version of the AlphaMissense database. 45 …”

Section: Methodsmentioning

confidence: 99%

Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes

Bittner,

Shi,

Zhao

et al. 2024

Ann Rheum Dis

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“…This result could potentially be attributed to AlphaMissense's ability to pinpoint functionally crucial sites (instead of simply evaluating the overall evolutionary conservation of a protein) [24]. It is noted that a few recent studies have shown that AlphaMissense can reliably classify subsets of variants that are known to affect molecular function [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene

Andhika,

Biswas,

Hardcastle

et al. 2024

Eur J Hum Genet

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The PAX6 gene encodes a highly-conserved transcription factor involved in eye development. Heterozygous loss-of-function variants in PAX6 can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that many PAX6 missense changes are presently classified as variants of uncertain significance. While computational tools can be used to assess the effect of genetic alterations, the accuracy of their predictions varies. Here, we evaluated and optimised the performance of computational prediction tools in relation to PAX6 missense variants. Through inspection of publicly available resources (including HGMD, ClinVar, LOVD and gnomAD), we identified 241 PAX6 missense variants that were used for model training and evaluation. The performance of ten commonly used computational tools was assessed and a threshold optimization approach was utilized to determine optimal cut-off values. Validation studies were subsequently undertaken using PAX6 variants from a local database. AlphaMissense, SIFT4G and REVEL emerged as the best-performing predictors; the optimized thresholds of these tools were 0.967, 0.025, and 0.772, respectively. Combining the prediction from these top-three tools resulted in lower performance compared to using AlphaMissense alone. Tailoring the use of computational tools by employing optimized thresholds specific to PAX6 can enhance algorithmic performance. Our findings have implications for PAX6 variant interpretation in clinical settings.

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“…24 It is noted that a few recent studies have shown that AlphaMissense can reliably classify subsets of variants that are known to affect molecular function. [46][47][48] The present study has several limitations, including the availability of a relatively small number of presumed pathogenic variants due to the rarity of PAX6-related disease. Additionally, we were unable to exclude the possibility that some of the studied genetic variants may have been utilized for training some of the evaluated tools.…”

Section: Discussionmentioning

confidence: 99%

Using computational approaches to enhance the interpretation of missense variants in thePAX6gene

Andhika,

Biswas,

Hardcastle

et al. 2023

Preprint

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PurposeThePAX6gene encodes a highly-conserved transcription factor involved in eye development. Heterozygous loss-of-function variants inPAX6can cause a range of ophthalmic disorders including aniridia. A key molecular diagnostic challenge is that manyPAX6missense changes are presently classified as variants of uncertain significance. While computational tools can be used to assess the effect of genetic alterations, the accuracy of their predictions varies. Here, we evaluated and optimised the performance of computational prediction tools in relation toPAX6missense variants.MethodsThrough inspection of publicly available resources (including HGMD, ClinVar, LOVD and gnomAD), we identified 241PAX6missense variants that were used for model training and evaluation. The performance of ten commonly-used computational tools was assessed and a threshold optimization approach was utilized to determine optimal cut-off values. Validation studies were subsequently undertaken usingPAX6variants from a local database.ResultsAlphaMissense, SIFT4G and REVEL emerged as the best-performing predictors; the optimized thresholds of these tools were 0.967, 0.025, and 0.772, respectively. Combining the prediction from these top-three tools resulted in lower performance compared to using AlphaMissense alone.ConclusionTailoring the use of computational tools by employing optimized thresholds specific toPAX6can enhance algorithmic performance. Our findings have implications forPAX6variant interpretation in clinical settings.

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Lightway access to AlphaMissense data that demonstrates a balanced performance of this missense mutation predictor

Cited by 4 publications

References 39 publications

Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes

Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes

Using computational approaches to enhance the interpretation of missense variants in the PAX6 gene

Using computational approaches to enhance the interpretation of missense variants in thePAX6gene

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