rs373225685

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004840.3(ARHGEF6):c.2170G>A(p.Glu724Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000911 in 1,207,740 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

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 -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 link	c.2170G>A	p.Glu724Lys	missense_variant	Exon 21 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.2170G>A	p.Glu724Lys	missense_variant	Exon 21 of 22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 link	c.1708G>A	p.Glu570Lys	missense_variant	Exon 20 of 21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 link	c.1708G>A	p.Glu570Lys	missense_variant	Exon 20 of 21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33896

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183356

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67824

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.00000912

AC:

AN:

1096068

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

361514

show subpopulations

Gnomad4 AFR exome

AF:

0.0000759

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.00000714

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33896

show subpopulations

Gnomad4 AFR

AF:

0.0000326

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E724K variant in the ARHGEF6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E724K variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E724K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.2170G>A (aka E724K) might create a cryptic donor site in intron 21 which may supplant the natural donor site. We interpret E724K as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

.;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.4

.;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.99

.;.;D

Vest4

0.79

MVP

0.91

MPC

0.49

ClinPred

0.40

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.48

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