X-136669520-C-T

Variant names:

• chrX-136669520-C-T
• rs2076200444
• NM_004840.3:c.2152G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004840.3(ARHGEF6):​c.2152G>A​(p.Val718Ile) 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: 22)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

Genes affected

ARHGEF6 (HGNC:685): (Rac/Cdc42 guanine nucleotide exchange factor 6) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4140157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2152G>A	p.Val718Ile	missense_variant	Exon 21 of 22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2152G>A	p.Val718Ile	missense_variant	Exon 21 of 22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1690G>A	p.Val564Ile	missense_variant	Exon 20 of 21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1690G>A	p.Val564Ile	missense_variant	Exon 20 of 21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.2152G>A (p.Val718Ile) variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.13	T;T;T
Polyphen		0.85	.;.;P
Vest4		0.37
MutPred		0.26		.;.;Gain of catalytic residue at V718 (P = 0.0717);
MVP		0.85
MPC		0.74
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs2076200444; hg19: chrX-135751679;