rs75329154

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004840.3(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. 15/21 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
NM_004840.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.145

Publications

2 publications found

Variant links:

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]

ARHGEF6 Gene-Disease associations (from GenCC):

non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Orphanet, ClinGen, Illumina
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
congenital anomaly of kidney and urinary tract
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability, X-linked 46
Inheritance: XL Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
X-linked intellectual disability
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ARHGEF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 210253.

BS2

High AC in GnomAd4 at 164 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 link	c.685G>A	p.Val229Ile	missense_variant	Exon 6 of 22	ENST00000250617.7	NP_004831.1	Q15052-1Q8N4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARHGEF6	ENST00000250617.7 link	c.685G>A	p.Val229Ile	missense_variant	Exon 6 of 22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 link	c.223G>A	p.Val75Ile	missense_variant	Exon 5 of 21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 link	c.223G>A	p.Val75Ile	missense_variant	Exon 5 of 21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

164

AN:

111617

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000784

AC:

140

AN:

178667

AF XY:

0.000471

show subpopulations

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 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.:

Cov.:

AF XY:

0.000890

AC XY:

320

AN XY:

359524

show subpopulations

African (AFR)

AF:

0.00558

AC:

147

AN:

26344

American (AMR)

AF:

0.000142

AC:

AN:

35115

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19307

East Asian (EAS)

AF:

0.00537

AC:

162

AN:

30162

South Asian (SAS)

AF:

0.0000744

AC:

AN:

53795

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40409

Middle Eastern (MID)

AF:

0.000738

AC:

AN:

4065

European-Non Finnish (NFE)

AF:

0.000839

AC:

704

AN:

838695

Other (OTH)

AF:

0.00137

AC:

AN:

45898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00147

AC:

164

AN:

111669

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

33879

show subpopulations

African (AFR)

AF:

0.00358

AC:

110

AN:

30731

American (AMR)

AF:

0.000475

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00447

AC:

AN:

3579

South Asian (SAS)

AF:

0.00

AC:

AN:

2692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000565

AC:

AN:

53089

Other (OTH)

AF:

0.00197

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000958

Hom.:

Bravo

AF:

0.00169

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000907

AC:

110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Apr 20, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2014

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.89

BayesDel_noAF

Benign

-1.1

CADD

Benign

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.15

.;.;T

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.66

.;T;T

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0074

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

.;.;N

PhyloP100

0.14

PrimateAI

Benign

0.32

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

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.11

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over