X-136747580-C-G

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.262G>C(p.Asp88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,186,180 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00019 ( 0 hom., 9 hem., cov: 20)

Exomes 𝑓: 0.00018 ( 0 hom. 73 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

Publications

1 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=0.016631484).

BP6

Variant X-136747580-C-G is Benign according to our data. Variant chrX-136747580-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210252.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 20 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 link	c.262G>C	p.Asp88His	missense_variant	Exon 3 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.262G>C	p.Asp88His	missense_variant	Exon 3 of 22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 link	c.-201G>C		5_prime_UTR_variant	Exon 2 of 21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 link	c.-201G>C		5_prime_UTR_variant	Exon 2 of 21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

104819

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000864

Gnomad FIN

AF:

0.00182

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000773

Gnomad OTH

AF:

0.000728

GnomAD2 exomes

AF:

0.000355

AC:

AN:

183099

AF XY:

0.000459

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00234

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000183

AC:

198

AN:

1081322

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

AN XY:

348734

show subpopulations

African (AFR)

AF:

0.0000769

AC:

AN:

26015

American (AMR)

AF:

0.00

AC:

AN:

34989

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19071

East Asian (EAS)

AF:

0.00

AC:

AN:

29751

South Asian (SAS)

AF:

0.000297

AC:

AN:

53811

European-Finnish (FIN)

AF:

0.00249

AC:

AN:

39837

Middle Eastern (MID)

AF:

0.00172

AC:

AN:

4080

European-Non Finnish (NFE)

AF:

0.0000760

AC:

AN:

828424

Other (OTH)

AF:

0.000243

AC:

AN:

45344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000191

AC:

AN:

104858

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

28540

show subpopulations

African (AFR)

AF:

0.000106

AC:

AN:

28306

American (AMR)

AF:

0.000107

AC:

AN:

9379

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2591

East Asian (EAS)

AF:

0.00

AC:

AN:

3322

South Asian (SAS)

AF:

0.000868

AC:

AN:

2303

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

4955

Middle Eastern (MID)

AF:

0.00

AC:

AN:

201

European-Non Finnish (NFE)

AF:

0.0000773

AC:

AN:

51734

Other (OTH)

AF:

0.000719

AC:

AN:

1391

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

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

0.084

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.41

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

M_CAP

Benign

0.053

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

-0.23

PhyloP100

1.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.30

REVEL

Benign

0.23

Sift

Benign

0.23

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.054

MVP

0.79

MPC

0.33

ClinPred

0.029

GERP RS

3.6

Varity_R

0.26

gMVP

0.42

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-136747580-C-G

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