rs75329154

Positions:

• chrX-136732149-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000250617.7(ARHGEF6):​c.685G>A​(p.Val229Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,205,459 control chromosomes in the GnomAD database, including 2 homozygotes. There are 365 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., 45 hem., cov: 23)
  • Exomes 𝑓: 0.00099 (0 hom. 320 hem.)
• Consequence: ARHGEF6 ENST00000250617.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.145

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 (MetaRNN=0.0073628128).
• BP6: Variant X-136732149-C-T is Benign according to our data. Variant chrX-136732149-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210253.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chrX-136732149-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3	c.685G>A	p.Val229Ile	missense_variant	6/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7	c.685G>A	p.Val229Ile	missense_variant	6/22	1	NM_004840.3	ENSP00000250617	P1
ARHGEF6	ENST00000370622.5	c.223G>A	p.Val75Ile	missense_variant	5/21	1		ENSP00000359656
ARHGEF6	ENST00000370620.5	c.223G>A	p.Val75Ile	missense_variant	5/21	2		ENSP00000359654

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 164 AN: 111617 Hom.: 2 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33817

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000476

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00446

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000565

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000784 AC: 140 AN: 178667 Hom.: 0 AF XY: 0.000471 AC XY: 30 AN XY: 63657

Gnomad AFR exome AF: 0.00420

Gnomad AMR exome AF: 0.0000735

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00211

Gnomad SAS exome AF: 0.0000543

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.000680

GnomAD4 exome AF: 0.000995 AC: 1088 AN: 1093790 Hom.: 0 Cov.: 28 AF XY: 0.000890 AC XY: 320 AN XY: 359524

Gnomad4 AFR exome AF: 0.00558

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00537

Gnomad4 SAS exome AF: 0.0000744

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000839

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00147 AC: 164 AN: 111669 Hom.: 2 Cov.: 23 AF XY: 0.00133 AC XY: 45 AN XY: 33879

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.000475

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00447

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000565

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.000740 Hom.: 22

Bravo AF: 0.00169

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000907 AC: 110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 2014	The p.V229I variant (also known as c.685G>A), located in coding exon 6 of the ARHGEF6 gene, results from a G to A substitution at nucleotide position 685. The valine at codon 229 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs75329154. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0% (0/503) total male alleles studied.. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.08% (2/2443) total male alleles studied, having been observed in 0.18% (1/571) African American male alleles and 0.05% (1/1872) European American male alleles. This amino acid position is not conserved on species alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

ARHGEF6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Non-syndromic X-linked intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	11
DANN	Benign	0.34
DEOGEN2	Benign	0.15	.;.;T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.66	.;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.41	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.44	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.071
MVP		0.19
MPC		0.23
ClinPred		0.0016	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.11

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: rs75329154; hg19: chrX-135814308;