The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting

Abstract

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most out of HGMD data in each setting.

Inferring the molecular and phenotypic impact of amino acid variants with MutPred2

“…1c). The MutPred2 pathogenicity model was trained on a set of 53,180 pathogenic and 206,946 unlabeled (putatively neutral) variants obtained from the Human Gene Mutation Database (HGMD) 17 , SwissVar 18 , dbSNP 19 , and interspecies pairwise alignments. The model is a bagged ensemble of feed-forward neural networks 20 , each trained on a balanced subset of pathogenic and unlabeled variants.…”

Background splicing and genetic disease

“…and DMD were obtained from the database of aberrant splice sites (DBASS) the human genome mutation database (HGMD), the Leiden Open Variation Database online (LOVD) and by searching Pubmed (4,6,7).…”

“…Databases of aberrant splicing in cancer and of recursive splicing were also analysed and are described in the text. We used the HGMD http://www.hgmd.cf.ac.uk/ac/index.php and LOVD websites https://databases.lovd.nl/shared/genes (6,7) to clarify the exon nomenclature used in original reports and the BLAT tool (8) from the UCSC website http://genome.ucsc.edu/ (9) to obtain genome reference numbers for relevant splice sites.…”

Cases of Diffuse Large B-Cell Lymphoma With Functional Intron Mutations in the Tp53 Gene

“…Мутация расположена в 6 интроне гена ТР53 и, согласно данным The Human Cancer Mutation Database, относится к изменениям, влияющим на сплайсинг [7]. Хотя замена IVS6-36G>C расположена далеко от экзон/интронного стыка, где обычно находятся сайты сплайсинга, описаны другие механизмы влияния изменения нуклеотидной последовательности в некодирующих регионах на созревание молекулы мРНК.…”

“…Например, в Catalogue Of Somatic Mutations In Cancer, The TP53 UMD mutation database in human cancer (2017 release) и IARC TP53 mutation Database (2012 release) перечислены только аберрации в кодирующих последовательностях гена ТР53 [4][5][6]. Лишь небольшое число интронных мутаций гена ТР53 аннотировано в Human Gene Mutation Database [7].…”