rs34274521

Positions:

• chrX-136707012-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_004840.3(ARHGEF6):​c.942C>T​(p.His314=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,209,690 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00017 (0 hom. 60 hem.)
• Consequence: ARHGEF6 NM_004840.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=1.93 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF6	NM_004840.3	c.942C>T	p.His314=	synonymous_variant	9/22	ENST00000250617.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.942C>T	p.His314=	synonymous_variant	9/22	1	NM_004840.3	P1
ARHGEF6	ENST00000370622.5	c.480C>T	p.His160=	synonymous_variant	8/21	1
ARHGEF6	ENST00000370620.5	c.480C>T	p.His160=	synonymous_variant	8/21	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 17 AN: 112400 Hom.: 0 Cov.: 22 AF XY: 0.000145 AC XY: 5 AN XY: 34558

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000225

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 33 AN: 183222 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000167 AC: 183 AN: 1097290 Hom.: 0 Cov.: 30 AF XY: 0.000165 AC XY: 60 AN XY: 362700

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000151 AC: 17 AN: 112400 Hom.: 0 Cov.: 22 AF XY: 0.000145 AC XY: 5 AN XY: 34558

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000378

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000163

Gnomad4 NFE AF: 0.000225

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 15

Bravo AF: 0.0000869

EpiCase AF: 0.000273

EpiControl AF: 0.000119

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

Genetic Services Laboratory, University of Chicago

Jun 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.7
DANN	Benign	0.57

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: rs34274521; hg19: chrX-135789171;