Imperial College London
Alternate

ProfessorMichaelSternberg

Faculty of Natural Sciences, Department of Life Sciences

Director, Systems Biology and Bioinformatics Centre
 
 
 
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Contact

 

+44 (0)20 7594 5212m.sternberg Website

 
 
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Location

 

306Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{David:2021:10.1007/s00439-020-02246-z,
author = {David, A and Khanna, T and Hanna, G and Sternberg, M},
doi = {10.1007/s00439-020-02246-z},
journal = {Human Genetics},
pages = {805--812},
title = {Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants},
url = {http://dx.doi.org/10.1007/s00439-020-02246-z},
volume = {140},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The interpretation of human genetic variation is one of the greatest challenges of modern genetics. New approaches are urgently needed to prioritize variants, especially those that are rare or lack a definitive clinical interpretation. We examined 10,136,597 human missense genetic variants from GnomAD, ClinVar and UniProt. We were able to perform large-scale atom-based mapping and phenotype interpretation of 3,960,015 of these variants onto 18,874 experimental and 84,818 in house predicted three-dimensional coordinates of the human proteome. We demonstrate that 14% of amino acid substitutions from the GnomAD database that could be structurally analysed are predicted to affect protein structure (n = 568,548, of which 566,439 rare or extremely rare) and may, therefore, have a yet unknown disease-causing effect. The same is true for 19.0% (n = 6266) of variants of unknown clinical significance or conflicting interpretation reported in the ClinVar database. The results of the structural analysis are available in the dedicated web catalogue Missense3D-DB (http://missense3d.bc.ic.ac.uk/). For each of the 4 M variants, the results of the structural analysis are presented in a friendly concise format that can be included in clinical genetic reports. A detailed report of the structural analysis is also available for the non-experts in structural biology. Population frequency and predictions from SIFT and PolyPhen are included for a more comprehensive variant interpretation. This is the first large-scale atom-based structural interpretation of human genetic variation and offers geneticists and the biomedical community a new approach to genetic variant interpretation.
AU  - David,A
AU  - Khanna,T
AU  - Hanna,G
AU  - Sternberg,M
DO  - 10.1007/s00439-020-02246-z
EP  - 812
PY  - 2021///
SN  - 0340-6717
SP  - 805
TI  - Missense3D-DB web catalogue: an atom-based analysis and repository of 4M human protein-coding genetic variants
T2  - Human Genetics
UR  - http://dx.doi.org/10.1007/s00439-020-02246-z
UR  - https://link.springer.com/article/10.1007%2Fs00439-020-02246-z
UR  - http://hdl.handle.net/10044/1/86131
VL  - 140
ER  -
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