7-22150442-T-C

Position:

• chr7-22150442-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012294.5(RAPGEF5):​c.1849A>G​(p.Ile617Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: RAPGEF5 NM_012294.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14936689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF5	NM_012294.5	c.1849A>G	p.Ile617Val	missense_variant	18/26	ENST00000665637.1	NP_036426.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF5	ENST00000665637.1	c.1849A>G	p.Ile617Val	missense_variant	18/26		NM_012294.5	ENSP00000499535.1
RAPGEF5	ENST00000401957.6	c.940A>G	p.Ile314Val	missense_variant	8/16	1		ENSP00000384044.1
RAPGEF5	ENST00000344041.10	c.1390A>G	p.Ile464Val	missense_variant	18/26	5		ENSP00000343656.6

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.1390A>G (p.I464V) alteration is located in exon 18 (coding exon 15) of the RAPGEF5 gene. This alteration results from a A to G substitution at nucleotide position 1390, causing the isoleucine (I) at amino acid position 464 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0068
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.052
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.0030	B;B
Vest4		0.35
MutPred		0.39		.;Loss of catalytic residue at I464 (P = 0.0165);
MVP		0.068
MPC		0.12
ClinPred		0.59	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: chr7-22190060;