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Fig. 1 | BMC Medical Genomics

Fig. 1

From: GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Fig. 1

GeneTerpret workflow. The figure depicts the modules, their feeding databases, acceptable inputs, and the flow of information in the workflow. The main modules feed into the gene validity, VIP, and causality modules. Three sets of modules are available within GeneTerpret for gene validity exploration; (1) ExPhenosion module—accepts the phenotype as input; the number of super-classes to walk up can be customized; and outputs the connected phenotypes and their associated genes. This module works independently from other developed modules to extract the connected phenotypes to the selected phenotype and allow the analyst to explore the genes associated with related phenotypes; (2) CanGene modules—generate a list of candidate genes by compiling various types of evidence. The cross-species (zebrafish and mouse) modules accept the disease(s) by its/their MONDO ID(s) as the input(s) and generate a list of genes that their orthologue is associated with similar disease in animal models by checking the related databases. The Homology and Protein–Protein Interaction modules accept a list of known genes for a phenotype (if it is available); the Homology module returns the homologous genes (paralogues) to the genes in the known gene list. The Protein–Protein interaction module takes a similar approach to generate a list of genes that interact with the known disease genes. The analyst can select the number of interaction neighborhood levels (such as level-1, level-2, etc.) desired for this interpretation. The Gene Expression module accepts a list of relevant tissues as input and outputs the list of genes expressed in the selected tissue based on the expression cut-off threshold which is set by the analyst; (3) KING module—accepts a disease(s) (MONDO ID(s)) as the input and then outputs a list of genes associated with the said disease based on evidence obtained from Orphanet, OMIM, ClinVar, and MedGen databases. The validity module accepts the generated gene lists from the modules CanGene and KING, as well as ANNOVAR, annotated VCF file or the output of VIP module as an input. The output file is the VCF file including validity scores. VIP module has been developed based on ACMG guidelines [16]. This module annotates the variants with pathogenicity terms (PVS1, PS1, etc.) and justifies the assigned terms. The causality module integrates the output of validity and VIP modules and ranks the variants based on the number of evidence extracted from validity modules and pathogenicity terms from VIP. Simultaneously, an interactive graphical representation of the variants is generated which allows the analyst to select the desired variants by using a LASSO filter

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