rs1017941774

Variant names:

• chrX-136672033-T-C
• rs1017941774
• NM_004840.3:c.2122A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-136672033-T-C
• chrX-136672033-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004840.3(ARHGEF6):​c.2122A>G​(p.Ile708Val) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02770102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2122A>G	p.Ile708Val	missense_variant	Exon 20 of 22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2122A>G	p.Ile708Val	missense_variant	Exon 20 of 22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1660A>G	p.Ile554Val	missense_variant	Exon 19 of 21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1660A>G	p.Ile554Val	missense_variant	Exon 19 of 21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	14
DANN	Benign	0.41
DEOGEN2	Benign	0.083	.;.;T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.71	.;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	.;.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.39	N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.14
MutPred		0.16		.;.;Loss of sheet (P = 0.1398);
MVP		0.27
MPC		0.24
ClinPred		0.032	T
GERP RS		2.4
Varity_R		0.069
gMVP		0.036

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: rs1017941774; hg19: chrX-135754192;