What is the main contribution of SNPMuSiC to folded protein fitness?

its contributions perfectly integrate into the MutaFrame framework and provide fundamental information about the variant effects, since stability is well known to be one of the main contributions to folded protein fitness [24].

What is the format of the figure?

The ”json” and ”csv” buttons download the data in JSON and CSV formats, respectively, and the ”camera” button downloads the figure in SVG format.

How does SNPMuSiC classify a variant as deleterious?

DEOGEN2 classifies the variant as highly deleterious with a score of 0.906 (with respect to a threshold value of 0.5) and SNPMuSiC classifies it as strongly deleterious with a score 0.64 (with respect to a threshold value of 0).

What is the drawback of the SNPMuSiC predictor?

As a consequence, a drawback of this predictor is its inability to predict variants that are deleterious due to other factors than stability.

Why is SNPMuSiC able to predict deleterious variants?

The lesser performances of SNPMuSiC are likely related to its ability to only predict variants of which the deleteriousness is caused by stability issues of the 3D structure, as previously discussed [7].

Open AccessPosted Content10.1101/2021.06.03.446874

MutaFrame - an interpretative visualization framework for deleteriousness prediction of missense variants in the human exome

François Ancien, +4 more

- 03 Jun 2021

- bioRxiv

TL;DR: MundaFrame as discussed by the authors is a web-server that offers two deleteriousness prediction softwares, DEOGEN2 and SNPMuSiC, and is designed for bioinformaticians and medical researchers who want to gain insights into the origins of monogenic diseases.

Abstract: Motivation: High-throughput experiments are generating ever increasing amounts of various -omics data, so shedding new light on the link between human disorders, their genetic causes, and the related impact on protein behavior and structure. While numerous bioinformatics tools now exist that predict which variants in the human exome cause diseases, few tools predict the reasons why they might do so. Yet, understanding the impact of variants at the molecular level is a prerequisite for the rational development of targeted drugs or personalized therapies. Results: We present the updated MutaFrame webserver, which aims to meet this need. It offers two deleteriousness prediction softwares, DEOGEN2 and SNPMuSiC, and is designed for bioinformaticians and medical researchers who want to gain insights into the origins of monogenic diseases. It contains information at two levels for each human protein: its amino acid sequence and its 3-dimensional structure; we used the experimental structures whenever available, and modeled structures otherwise. MutaFrame also includes higher-level information, such as protein essentiality and protein-protein interactions. It has a user-friendly interface for the interpretation of results and a convenient visualization system for protein structures, in which the variant positions introduced by the user and other structural information are shown. In this way, MutaFrame aids our understanding of the pathogenic processes caused by single-site mutations and their molecular and contextual interpretation. Availability: Mutaframe webserver at http://mutaframe.com/

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Most frequently asked questions

1. What is the name of the SNPMuSiC?

To perform its predictions, SNPMuSiC uses a series of statistical potentials, which are coarse-grained mean force potentials widely applied in protein science [22].

2. What is the purpose of the mutaFrame utility?

MutaFrame does not only give DEOGEN2 and SNPMuSiC predictions on the target variant, but also average per-residue predictions on all possible variants in the target sequence, which is very useful to obtain a global view of the susceptibility of the protein to deleterious variants.

3. What is the effect of Arg228Cys on the prediction of a variant?

Arg228Cys is a known deleterious mutation [29, 30, 31] reported in gnomAD and ClinVar and its molecular effect results in a residual activity of about5% with respect to the wild type protein [29].

4. What is the main drawback of the MutaFrame tool?

MutaFrame provides two computational tools to cross reference different sources of information at the variant, gene, protein sequence, 3D structure, and phenotypic levels.

Table 1: List of features used by DEOGEN2 to predict the deleterious impact of variants. The sequence-based information is in blue and the contextual information in green. MSA means Multiple Sequence Alignments, and PFAM Protein Families.

Figure 8: Sphingomyelin phosphodiesterase (SMPD1) involved in the Niemann-Pick disease (PDB code 5JG8). (a) Environment of Arg 228, which interacts with Asp 210 through a salt bridge. (b) Environment of Trp 244, which forms a cation-π interaction with Arg 255 and a π-π interaction with Tyr 243.

Figure 5: (a) Window appearing when clicking on the VarCraft button. It is possible to label mutations in the DEOGEN2 heatmap (b) or in the DEOGEN2 scores distribution (c) using the ”Label Mutations” button. The ”Clear Mutations” button removes the label from the graphs. Here, the variant C106V of Uniprot P36897 was labelled.

Figure 1: The capabilities of the MutaFrame webserver at the mapping (a), variant effect interpretation (b) and 3D structure visualization (c) levels (see also Supplementary Material).

Table 2: List of options for the MutaFrame protein structure visualizer.

Table 3: List of all the features used in the SNPMuSiC model to predict variant deleteriousness. In green, the structure-based, stability-driven features. In blue, the sequence-based, evolutionary-driven feature.

Citations

•Journal Article•10.1016/j.jmb.2022.167567

Venus: Elucidating the Impact of Amino Acid Variants on Protein Function Beyond Structure Destabilisation

Matteo P. Ferla, +4 more

- 01 Mar 2022

- Journal of Molecular Biology

TL;DR: Ven as discussed by the authors is a web application which, given a protein substitution, rapidly estimates the predicted effect on protein stability of the variant, flags if the variant affects a post-translational modification site, a predicted linear motif or known annotation.

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•Journal Article•10.1016/j.csbj.2022.12.031

MUG: A mutation overview of GPCR subfamily A17 receptors

Ana B Caniceiro, +4 more

- 01 Dec 2022

- Computational and structural biotechnolo...

TL;DR: A comprehensive and detailed computational framework, MUG (Mutations Understanding GPCRs) as discussed by the authors , was constructed, illustrating key reported mutations and their effect on receptors of the subfamily A17 of GPCR genes.

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References

•Journal Article•10.1093/NAR/22.22.4673

Clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice

Julie D. Thompson, +2 more

- 11 Nov 1994

- Nucleic Acids Research

TL;DR: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved and modifications are incorporated into a new program, CLUSTAL W, which is freely available.

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•Journal Article•10.1038/NATURE15393

A global reference for human genetic variation.

Adam Auton, +517 more

- 01 Oct 2015

- Nature

TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.

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A global reference for human genetic variation

Adam Auton, +479 more

- 01 Oct 2015

TL;DR: The 1000 Genomes Project as mentioned in this paper provided a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and reported the completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole genome sequencing, deep exome sequencing and dense microarray genotyping.

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•Journal Article•10.1093/NAR/GKH131

UniProt: the Universal Protein knowledgebase

Rolf Apweiler, +14 more

- 01 Jan 2004

- Nucleic Acids Research

TL;DR: The Swiss-Prot, TrEMBL and PIR protein database activities have united to form the Universal Protein Knowledgebase (UniProt), which is to provide a comprehensive, fully classified, richly and accurately annotated protein sequence knowledgebase, with extensive cross-references and query interfaces.

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•Journal Article•10.1073/PNAS.89.22.10915

Amino acid substitution matrices from protein blocks

Steven Henikoff, +1 more

- 15 Nov 1992

- Proceedings of the National Academy of S...

TL;DR: This work has derived substitution matrices from about 2000 blocks of aligned sequence segments characterizing more than 500 groups of related proteins, leading to marked improvements in alignments and in searches using queries from each of the groups.

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MutaFrame - an interpretative visualization framework for deleteriousness prediction of missense variants in the human exome

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AI Agents for this Paper

Most frequently asked questions

1. What is the name of the SNPMuSiC?

2. What is the purpose of the mutaFrame utility?

3. What is the effect of Arg228Cys on the prediction of a variant?

4. What is the main drawback of the MutaFrame tool?

5. What is the main contribution of SNPMuSiC to folded protein fitness?

6. What is the format of the figure?

7. How does SNPMuSiC classify a variant as deleterious?

8. What is the drawback of the SNPMuSiC predictor?

9. Why is SNPMuSiC able to predict deleterious variants?

Figures

Citations

Venus: Elucidating the Impact of Amino Acid Variants on Protein Function Beyond Structure Destabilisation

MUG: A mutation overview of GPCR subfamily A17 receptors

References

Clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice

A global reference for human genetic variation.

A global reference for human genetic variation

UniProt: the Universal Protein knowledgebase

Amino acid substitution matrices from protein blocks

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