X-136687987-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004840.3(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. 14/21 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
NM_004840.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.90

Publications

0 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: Orphanet, ClinGen, Illumina
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 -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 VariationId is 210249.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 19 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
ARHGEF6	NM_004840.3	MANE Select	c.1190C>G	p.Thr397Ser	missense	Exon 11 of 22	NP_004831.1
ARHGEF6	NM_001440994.1		c.1271C>G	p.Thr424Ser	missense	Exon 12 of 23	NP_001427923.1
ARHGEF6	NM_001440995.1		c.1190C>G	p.Thr397Ser	missense	Exon 11 of 22	NP_001427924.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGEF6	ENST00000250617.7	TSL:1 MANE Select	c.1190C>G	p.Thr397Ser	missense	Exon 11 of 22	ENSP00000250617.6
ARHGEF6	ENST00000370622.5	TSL:1	c.728C>G	p.Thr243Ser	missense	Exon 10 of 21	ENSP00000359656.1
ARHGEF6	ENST00000881407.1		c.1271C>G	p.Thr424Ser	missense	Exon 12 of 23	ENSP00000551466.1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

112332

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000601

AC:

110

AN:

183053

AF XY:

0.00101

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 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

African (AFR)

AF:

0.0000767

AC:

AN:

26083

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19264

East Asian (EAS)

AF:

0.00

AC:

AN:

30129

South Asian (SAS)

AF:

0.00571

AC:

307

AN:

53779

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

827255

Other (OTH)

AF:

0.000197

AC:

AN:

45580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000169

AC:

AN:

112384

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

AN XY:

34554

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30990

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00704

AC:

AN:

2699

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6117

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53294

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.078

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.75

PhyloP100

2.9

PrimateAI

Benign

0.39

PROVEAN

Benign

0.89

REVEL

Benign

0.10

Sift

Benign

0.42

Sift4G

Benign

0.47

Polyphen

0.0020

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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