Table 1.

Advanced features in the RD‐Connect Genome‐Phenome Analysis Platform for variant filtration, prioritization and interpretation

Objective	Method	Tools/Resources
Variant filtration	Generate candidate gene lists on‐the‐fly via APIs	PanelApp (Martin et al., 2019) Reactome (Fabregat et al., 2018) HPO (Kohler et al., 2021) DisGeNET (Piñero et al., 2020) OMIM (Amberger et al., 2015)
Variant filtration	Identify variants in long runs of homozygosity	Runs of homozygosity >500 kb, 1 Mb, and 2 Mb in length are identified as described in Kancheva et al. (2016)
Variant filtration	Remove common variants	Filter by allele frequency from: RD‐Connect Internal Frequency gnomAD (Karczewski et al., 2020) 1000 Genomes Project (Genomes Project et al., 2015)
Variant prioritization	Score and rank list of candidate variants according to supplied HPO terms	Exomiser (Smedley et al., 2015)
Variant Iinterpretation	Hyperlinks to appropriate records in external resources	HGMD (Stenson et al., 2020) ClinVar (Landrum et al., 2020) VarSeak (www.varseak.bio) DisGeNET (Piñero et al., 2020) HmtDB (Clima et al., 2017)
Variant interpretation	Classify according to ACMG Criteria	Link from variant to Varsome (Kopanos et al., 2019)
	Search for variant in patient cohort	This internal search tool allows querying for specific genes or variants of interest across a cohort of accessible samples in the platform
	Tagging Variants	Users can tag variants in the platform and attribute a clinical significance, in accordance with the ACMG guidelines, for a specific patient and disorder. These tagged variants are visible to all other users and may be relevant for interpretation of their cases.
Gene discovery	Internal data discovery	Search within RD‐Connect GPAP cohorts Search across all RD‐Connect GPAP participants Internal matchmaking
	External data discovery	Matchmaker Exchange API (Buske et al., 2015) Beacon v1 API (Fiume et al., 2019)