7-22131087-G-A

Position:

• chr7-22131087-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_012294.5(RAPGEF5):​c.2431C>T​(p.His811Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPGEF5 NM_012294.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.14

Genes affected

RAPGEF5 (HGNC:16862): (Rap guanine nucleotide exchange factor 5) Members of the RAS (see HRAS; MIM 190020) subfamily of GTPases function in signal transduction as GTP/GDP-regulated switches that cycle between inactive GDP- and active GTP-bound states. Guanine nucleotide exchange factors (GEFs), such as RAPGEF5, serve as RAS activators by promoting acquisition of GTP to maintain the active GTP-bound state and are the key link between cell surface receptors and RAS activation (Rebhun et al., 2000 [PubMed 10934204]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 7-22131087-G-A is Pathogenic according to our data. Variant chr7-22131087-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1693113.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF5	NM_012294.5	c.2431C>T	p.His811Tyr	missense_variant	24/26	ENST00000665637.1	NP_036426.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1	c.2431C>T	p.His811Tyr	missense_variant	24/26		NM_012294.5	ENSP00000499535.1
RAPGEF5	ENST00000401957.6	c.1522C>T	p.His508Tyr	missense_variant	14/16	1		ENSP00000384044.1
RAPGEF5	ENST00000344041.10	c.1972C>T	p.His658Tyr	missense_variant	24/26	5		ENSP00000343656.6
RAPGEF5	ENST00000488366.1	n.50C>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dilated cardiomyopathy 1A Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Cytogenetics- Mohapatra Lab, Banaras Hindu University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.82
MutPred		0.58		.;Gain of catalytic residue at I657 (P = 0.0375);.;
MVP		0.31
MPC		0.67
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-22170705;