Variant chrX-136687987-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000250617.7(ARHGEF6):c.1190C>G(p.Thr397Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,194,251 control chromosomes in the GnomAD database, including 2 homozygotes. There are 192 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00029 ( 2 hom. 181 hem. )

Consequence

ARHGEF6
ENST00000250617.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.90

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051814914).

BP6

Variant X-136687987-G-C is Benign according to our data. Variant chrX-136687987-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 210249.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136687987-G-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.1190C>G	p.Thr397Ser	missense_variant	11/22	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.1190C>G	p.Thr397Ser	missense_variant	11/22	1	NM_004840.3	ENSP00000250617	P1	Q15052-1
ARHGEF6	ENST00000370622.5 linkuse as main transcript	c.728C>G	p.Thr243Ser	missense_variant	10/21	1		ENSP00000359656		Q15052-2
ARHGEF6	ENST00000370620.5 linkuse as main transcript	c.728C>G	p.Thr243Ser	missense_variant	10/21	2		ENSP00000359654		Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

112332

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

AN XY:

34492

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00739

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000601

AC:

110

AN:

183053

Hom.:

AF XY:

0.00101

AC XY:

AN XY:

67605

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000295

AC:

319

AN:

1081867

Hom.:

Cov.:

AF XY:

0.000519

AC XY:

181

AN XY:

348867

show subpopulations

Gnomad4 AFR exome

AF:

0.0000767

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00571

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.000197

GnomAD4 genome

AF:

0.000169

AC:

AN:

112384

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

AN XY:

34554

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.078

.;.;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.70

.;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

.;.;N

MutationTaster

Benign

0.53

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

0.89

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0020

.;.;B

Vest4

0.031

MutPred

0.31

.;.;Gain of disorder (P = 0.1127);

MVP

0.63

MPC

0.26

ClinPred

0.034

GERP RS

5.1

Varity_R

0.18

gMVP

0.16

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

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