Variant chrX-136672062-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_004840.3(ARHGEF6):c.2093T>C(p.Ile698Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,209,469 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000026 ( 0 hom. 13 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: 8.20

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38976017).

BS2

High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.2093T>C	p.Ile698Thr	missense_variant	20/22	ENST00000250617.7	NP_004831.1	Q15052-1Q8N4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARHGEF6	ENST00000250617.7 linkuse as main transcript	c.2093T>C	p.Ile698Thr	missense_variant	20/22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 linkuse as main transcript	c.1631T>C	p.Ile544Thr	missense_variant	19/21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 linkuse as main transcript	c.1631T>C	p.Ile544Thr	missense_variant	19/21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34178

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1097477

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

362855

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000285

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34178

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.0092

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

.;.;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.62

.;.;P

Vest4

0.49

MutPred

0.45

.;.;Loss of stability (P = 0.0385);

MVP

0.80

MPC

0.39

ClinPred

0.86

GERP RS

6.0

Varity_R

0.38

gMVP

0.23

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

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