Variant X-136672033-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004840.3(ARHGEF6):c.2122A>C(p.Ile708Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,206,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10381156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 link	c.2122A>C	p.Ile708Leu	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 link	c.2122A>C	p.Ile708Leu	missense_variant	20/22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 link	c.1660A>C	p.Ile554Leu	missense_variant	19/21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 link	c.1660A>C	p.Ile554Leu	missense_variant	19/21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34274

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183498

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67928

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1094630

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

360250

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34274

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.2122A>C (p.I708L) alteration is located in exon 20 (coding exon 20) of the ARHGEF6 gene. This alteration results from a A to C substitution at nucleotide position 2122, causing the isoleucine (I) at amino acid position 708 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.19

.;.;T

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

.;.;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.68

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.39

MutPred

0.17

.;.;Loss of sheet (P = 0.0357);

MVP

0.49

MPC

0.28

ClinPred

0.12

GERP RS

2.4

Varity_R

0.27

gMVP

0.10

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