rs138342895

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.1480-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,188,161 control chromosomes in the GnomAD database, including 5 homozygotes. There are 305 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 2 hom., 114 hem., cov: 23)

Exomes 𝑓: 0.00060 ( 3 hom. 191 hem. )

Consequence

ARHGEF6
NM_004840.3 splice_region, intron

Scores

Splicing: ADA: 0.0002239

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.558

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant X-136681971-A-G is Benign according to our data. Variant chrX-136681971-A-G is described in ClinVar as [Benign]. Clinvar id is 128448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 462 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 link	c.1480-3T>C		splice_region_variant, intron_variant	Intron 13 of 21	ENST00000250617.7	NP_004831.1	Q15052-1Q8N4Q3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARHGEF6	ENST00000250617.7 link	c.1480-3T>C	splice_region_variant, intron_variant	Intron 13 of 21	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 link	c.1018-3T>C	splice_region_variant, intron_variant	Intron 12 of 20	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 link	c.1018-3T>C	splice_region_variant, intron_variant	Intron 12 of 20	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

462

AN:

111978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

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:

0.000263

Gnomad OTH

AF:

0.00598

GnomAD2 exomes

AF:

0.00136

AC:

249

AN:

183031

AF XY:

0.000977

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000208

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000596

AC:

641

AN:

1076130

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

191

AN XY:

343224

show subpopulations

African (AFR)

AF:

0.0151

AC:

393

AN:

25981

American (AMR)

AF:

0.00117

AC:

AN:

35164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19228

East Asian (EAS)

AF:

0.00

AC:

AN:

30094

South Asian (SAS)

AF:

0.0000373

AC:

AN:

53646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40270

Middle Eastern (MID)

AF:

0.00221

AC:

AN:

4073

European-Non Finnish (NFE)

AF:

0.000159

AC:

131

AN:

822285

Other (OTH)

AF:

0.00143

AC:

AN:

45389

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00412

AC:

462

AN:

112031

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

114

AN XY:

34217

show subpopulations

African (AFR)

AF:

0.0138

AC:

425

AN:

30884

American (AMR)

AF:

0.00132

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3604

South Asian (SAS)

AF:

0.00

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000263

AC:

AN:

53144

Other (OTH)

AF:

0.00590

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00223

Hom.:

Bravo

AF:

0.00494

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ARHGEF6-related disorder

Benign:1

Aug 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.5

(source)

DANN

Benign

0.72

PhyloP100

0.56

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.028

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over