chrX-136669534-C-T

Position:

• chrX-136669534-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004840.3(ARHGEF6):​c.2138G>A​(p.Ser713Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000824 in 1,092,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: ARHGEF6 NM_004840.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.93

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 -4 ACMG points.

• 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.2138G>A	p.Ser713Asn	missense_variant, splice_region_variant	21/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.2138G>A	p.Ser713Asn	missense_variant, splice_region_variant	21/22	1	NM_004840.3	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	c.1676G>A	p.Ser559Asn	missense_variant, splice_region_variant	20/21	1		ENSP00000359656.1
ARHGEF6	ENST00000370620.5	c.1676G>A	p.Ser559Asn	missense_variant, splice_region_variant	20/21	2		ENSP00000359654.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000824 AC: 9 AN: 1092046 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 357646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000837

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome Cov.: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 07, 2024

The c.2138G>A (p.S713N) alteration is located in exon 21 (coding exon 21) of the ARHGEF6 gene. This alteration results from a G to A substitution at nucleotide position 2138, causing the serine (S) at amino acid position 713 to be replaced by an asparagine (N). 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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.9	.;.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.84
MutPred		0.22		.;.;Loss of sheet (P = 0.0181);
MVP		0.89
MPC		0.71
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.53

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: chrX-135751693;