rs35106300

Positions:

chrX-136745320-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004840.3(ARHGEF6):c.362G>A(p.Arg121His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,209,615 control chromosomes in the GnomAD database, including 17 homozygotes. There are 2,151 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., 121 hem., cov: 23)

Exomes 𝑓: 0.0058 ( 16 hom. 2030 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.744

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059680343).

BP6

Variant X-136745320-C-T is Benign according to our data. Variant chrX-136745320-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136745320-C-T is described in Lovd as [Likely_benign]. Variant chrX-136745320-C-T is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 121 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.362G>A	p.Arg121His	missense_variant	4/22	ENST00000250617.7	NP_004831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF6	ENST00000250617.7 linkuse as main transcript	c.362G>A	p.Arg121His	missense_variant	4/22	1	NM_004840.3	ENSP00000250617	P1	Q15052-1
ARHGEF6	ENST00000370622.5 linkuse as main transcript	c.-101G>A		5_prime_UTR_variant	3/21	1		ENSP00000359656		Q15052-2
ARHGEF6	ENST00000370620.5 linkuse as main transcript	c.-101G>A		5_prime_UTR_variant	3/21	2		ENSP00000359654		Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

441

AN:

111879

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

121

AN XY:

34077

show subpopulations

Gnomad AFR

AF:

0.000813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00297

Gnomad FIN

AF:

0.00516

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00656

Gnomad OTH

AF:

0.00264

GnomAD3 exomes

AF:

0.00463

AC:

850

AN:

183462

Hom.:

AF XY:

0.00471

AC XY:

320

AN XY:

67898

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00299

Gnomad FIN exome

AF:

0.00757

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00530

GnomAD4 exome

AF:

0.00582

AC:

6389

AN:

1097685

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

2030

AN XY:

363063

show subpopulations

Gnomad4 AFR exome

AF:

0.000644

Gnomad4 AMR exome

AF:

0.00287

Gnomad4 ASJ exome

AF:

0.000258

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00260

Gnomad4 FIN exome

AF:

0.00911

Gnomad4 NFE exome

AF:

0.00658

Gnomad4 OTH exome

AF:

0.00462

GnomAD4 genome

AF:

0.00394

AC:

441

AN:

111930

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

121

AN XY:

34138

show subpopulations

Gnomad4 AFR

AF:

0.000811

Gnomad4 AMR

AF:

0.00227

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00298

Gnomad4 FIN

AF:

0.00516

Gnomad4 NFE

AF:

0.00657

Gnomad4 OTH

AF:

0.00261

Alfa

AF:

0.00561

Hom.:

271

Bravo

AF:

0.00338

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00762

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00476

AC:

ExAC

AF:

0.00506

AC:

614

EpiCase

AF:

0.00573

EpiControl

AF:

0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

ARHGEF6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

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

Intellectual disability, X-linked 46

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.80

M_CAP

Benign

0.012

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.74

REVEL

Benign

0.026

Sift

Benign

0.076

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.014

MVP

0.54

MPC

0.35

ClinPred

0.0060

GERP RS

3.5

Varity_R

0.073

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over