NM_004840.3:c.362G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004840.3(ARHGEF6):c.362G>A(p.Arg121His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,209,615 control chromosomes in the GnomAD database, including 17 homozygotes. There are 2,151 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., 121 hem., cov: 23)

Exomes 𝑓: 0.0058 ( 16 hom. 2030 hem. )

Consequence

ARHGEF6
NM_004840.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.744

Publications

7 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: Illumina, Orphanet, ClinGen
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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059680343).

BP6

Variant X-136745320-C-T is Benign according to our data. Variant chrX-136745320-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 441 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004840.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF6	NM_004840.3	MANE Select	c.362G>A	p.Arg121His	missense	Exon 4 of 22	NP_004831.1	Q15052-1
ARHGEF6	NM_001440994.1		c.362G>A	p.Arg121His	missense	Exon 4 of 23	NP_001427923.1
ARHGEF6	NM_001440995.1		c.362G>A	p.Arg121His	missense	Exon 4 of 22	NP_001427924.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGEF6	ENST00000250617.7	TSL:1 MANE Select	c.362G>A	p.Arg121His	missense	Exon 4 of 22	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5	TSL:1	c.-101G>A		5_prime_UTR	Exon 3 of 21	ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000881407.1		c.362G>A	p.Arg121His	missense	Exon 4 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

441

AN:

111879

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000813

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00297

Gnomad FIN

AF:

0.00516

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00656

Gnomad OTH

AF:

0.00264

GnomAD2 exomes

AF:

0.00463

AC:

850

AN:

183462

AF XY:

0.00471

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00757

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00530

GnomAD4 exome

AF:

0.00582

AC:

6389

AN:

1097685

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

2030

AN XY:

363063

show subpopulations

African (AFR)

AF:

0.000644

AC:

AN:

26392

American (AMR)

AF:

0.00287

AC:

101

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.000258

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00260

AC:

141

AN:

54139

European-Finnish (FIN)

AF:

0.00911

AC:

369

AN:

40518

Middle Eastern (MID)

AF:

0.00218

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00658

AC:

5534

AN:

841640

Other (OTH)

AF:

0.00462

AC:

213

AN:

46081

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

241

482

723

964

1205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00394

AC:

441

AN:

111930

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

121

AN XY:

34138

show subpopulations

African (AFR)

AF:

0.000811

AC:

AN:

30827

American (AMR)

AF:

0.00227

AC:

AN:

10575

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3596

South Asian (SAS)

AF:

0.00298

AC:

AN:

2682

European-Finnish (FIN)

AF:

0.00516

AC:

AN:

6010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00657

AC:

349

AN:

53157

Other (OTH)

AF:

0.00261

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00523

Hom.:

274

Bravo

AF:

0.00338

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00762

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00476

AC:

ExAC

AF:

0.00506

AC:

614

EpiCase

AF:

0.00573

EpiControl

AF:

0.00569

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

ARHGEF6-related disorder (1)

Genetic developmental and epileptic encephalopathy (1)

Intellectual disability (1)

Intellectual disability, X-linked 46 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.80

M_CAP

Benign

0.012

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.74

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.74

REVEL

Benign

0.026

Sift

Benign

0.076

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.014

MVP

0.54

MPC

0.35

ClinPred

0.0060

GERP RS

3.5

Varity_R

0.073

gMVP

0.19

Mutation Taster

=297/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over