Genotypic summaries to assist variant interpretation
DECIPHER provides a suite of tools to assist in assessing the
pathogenicity of variants, including genome and protein browsers.
Protein browser: A protein browser is available for
protein-coding genes, showing a genotypic summary which helps users to
determine if a variant is located in a mutational hot spot or
established functional domain (Fig. 5A). The protein browser is fully
interactive and is customisable via a settings menu. In the centre of
the protein browser, Pfam domains (Mistry et al ., 2021) are
displayed allowing users to identify distinct functional/structural
elements of the protein. Clinically relevant variants from DECIPHER and
ClinVar are plotted above and below the Pfam domains, with annotated
pathogenicity and predicted molecular consequence (e.g. missense, likely
loss-of-function (LOF)) indicated through colouring. In addition to the
location of the variants being shown, for likely LOF variants, the
location of the protein truncating codon is indicated, since this
information is essential in determining if a transcript will escape
nonsense mediated decay (NMD). A predicted (NMD) track is also
displayed. The location of variation in the general population is shown
through display of gnomAD missense and LOF tracks. Regional missense
constraint data is also available (regional missense constraint improves
variant deleteriousness prediction, Samocha et al .,
https://www.biorxiv.org/content/10.1101/148353v1), in addition to exon
structure. Protein secondary structures (e.g. locations of helices and
turns) and the locations of 3D structures (where available from the
Protein Data Bank in Europe (PDBe)) are displayed at the bottom of the
protein browser. Clicking on these 3D structures will display an
interactive 3D protein viewer (Marco Biasini, 2015, pv v1.8.1. Zenodo.
https://doi.org/10.5281/zenodo.20980) which provides zooming, panning
and rotation, and hovering over an amino acid with a pointing device
identifies the visualised amino acid and position (similar behaviour
exists for ligands). DECIPHER variants are shown in this 3D view,
allowing users to determine, for example if the variants are all within
a DNA binding pocket or enzyme active site.
When looking at the protein browser from a patient record with a
sequence variant, the location of the patient’s variant is displayed by
a vertical line, allowing easy orientation. In the case of a patient
with a CNV, the protein browser is accessible from the CNV’s genes tab,
which displays a table of genes that overlap the CNV, along with other
relevant information such as gene/disease association information and
predictive scores. Clicking on a row displays further information about
that gene, including the protein browser. An additional track is shown
on the protein browser, indicating which part of the protein overlaps
the CNV.
Genome browser: The Genoverse genome browser
(http://genoverse.org), developed by
the DECIPHER team, is a portable, interactive, customizable genome
browser which allows the user to explore data. It displays a number of
tracks containing information relevant to variant pathogenicity
assessment such as genes associated with disease phenotypes (as curated
and maintained by Online Mendelian Inheritance in Man (OMIM,https://omim.org, Amberger etal., 2019), protein ortholog sequences from Ensembl indicating
conversation, transcripts (as maintained by Ensembl), and regional
missense constraint. Information from population resources such as
gnomAD and Database of Genomic Variants (DGV) Gold (Church et
al ., 2010) are displayed to enable users to determine if their
patient’s variant has been observed in healthy individuals. Disease
relevant variant tracks are also available, which include DECIPHER
sequence variants and CNVs, ClinVar sequence and structural variants,
and variants from Human Gene Mutation Database (HGMD) public (Stensonet al ., 2020). The tracks which are displayed by default are
tailored according to the type of variant being assessed.