X-136675018-C-A

Position:

• chrX-136675018-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004840.3(ARHGEF6):​c.2024G>T​(p.Gly675Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,096,939 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000073 (0 hom. 4 hem.)
• Consequence: ARHGEF6 NM_004840.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.24

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23490068).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.2024G>T	p.Gly675Val	missense_variant	19/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2024G>T	p.Gly675Val	missense_variant	19/22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1562G>T	p.Gly521Val	missense_variant	18/21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1562G>T	p.Gly521Val	missense_variant	18/21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1096939 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 362331

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000652

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.2024G>T (p.G675V) alteration is located in exon 19 (coding exon 19) of the ARHGEF6 gene. This alteration results from a G to T substitution at nucleotide position 2024, causing the glycine (G) at amino acid position 675 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked 46 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 18, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.13	.;.;B
Vest4		0.27
MutPred		0.22		.;.;Loss of disorder (P = 0.0492);
MVP		0.67
MPC		0.37
ClinPred		0.32	T
GERP RS		3.6
Varity_R		0.30
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1426557239; hg19: chrX-135757177;