12-57613023-C-G

Variant names:

• chr12-57613023-C-G
• NM_182947.4:c.191C>G

Variant summary

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

The NM_182947.4(ARHGEF25):​c.191C>G​(p.Ser64Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGEF25 NM_182947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

Genes affected

ARHGEF25 (HGNC:30275): (Rho guanine nucleotide exchange factor 25) Rho GTPases alternate between an inactive GDP-bound state and an active GTP-bound state, and GEFs facilitate GDP/GTP exchange. This gene encodes a guanine nucleotide exchange factor (GEF) which interacts with Rho GTPases involved in contraction of vascular smooth muscles, regulation of responses to angiotensin II and lens cell differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ENSG00000224713 (HGNC:):

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=0.25617653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF25	NM_182947.4	c.191C>G	p.Ser64Cys	missense_variant	Exon 2 of 15	ENST00000286494.9	NP_891992.3
ARHGEF25	NM_001111270.3	c.308C>G	p.Ser103Cys	missense_variant	Exon 3 of 16		NP_001104740.2
ARHGEF25	NM_001347933.2	c.191C>G	p.Ser64Cys	missense_variant	Exon 2 of 14		NP_001334862.2
ARHGEF25	NR_046223.2	n.699-18C>G		intron_variant	Intron 2 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF25	ENST00000286494.9	c.191C>G	p.Ser64Cys	missense_variant	Exon 2 of 15	1	NM_182947.4	ENSP00000286494.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308C>G (p.S103C) alteration is located in exon 3 (coding exon 3) of the ARHGEF25 gene. This alteration results from a C to G substitution at nucleotide position 308, causing the serine (S) at amino acid position 103 to be replaced by a cysteine (C). 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	0.090
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Benign	0.087
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	.;D
Vest4		0.39
MutPred		0.28		.;Loss of glycosylation at S64 (P = 3e-04);
MVP		0.57
MPC		0.82
ClinPred		0.91	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.56

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: chr12-58006806;