Genetic Variant ARHGAP6:c.589-40830A>G (chrX-11295537-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_013427.3(ARHGAP6):c.589-40830A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 110,548 control chromosomes in the GnomAD database, including 5,216 homozygotes. There are 10,168 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 5216 hom., 10168 hem., cov: 22)

Consequence

ARHGAP6
NM_013427.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.807

Publications

5 publications found

Variant links:

Genes affected

ARHGAP6 (HGNC:676): (Rho GTPase activating protein 6) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ARHGAP6 links:

AMELX (HGNC:461): (amelogenin X-linked) This gene encodes a member of the amelogenin family of extracellular matrix proteins. Amelogenins are involved in biomineralization during tooth enamel development. Mutations in this gene cause X-linked amelogenesis imperfecta. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

AMELX Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 1E
Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AMELX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3 link	c.589-40830A>G		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2	O43182-1
AMELX	NM_001142.2 link	c.54+695T>C		intron_variant	Intron 2 of 5	ENST00000380714.7	NP_001133.1	Q99217-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP6	ENST00000337414.9 link	c.589-40830A>G		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4		O43182-1
AMELX	ENST00000380714.7 link	c.54+695T>C		intron_variant	Intron 2 of 5	1	NM_001142.2	ENSP00000370090.3		Q99217-1

Frequencies

GnomAD3 genomes

AF:

0.325

AC:

35928

AN:

110493

Hom.:

5213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.555

Gnomad AMI

AF:

0.0338

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.0246

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.293

Gnomad MID

AF:

0.371

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.300

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.325

AC:

35974

AN:

110548

Hom.:

5216

Cov.:

AF XY:

0.310

AC XY:

10168

AN XY:

32804

show subpopulations

African (AFR)

AF:

0.556

AC:

16846

AN:

30297

American (AMR)

AF:

0.192

AC:

2011

AN:

10451

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

817

AN:

2635

East Asian (EAS)

AF:

0.0247

AC:

AN:

3520

South Asian (SAS)

AF:

0.222

AC:

580

AN:

2611

European-Finnish (FIN)

AF:

0.293

AC:

1710

AN:

5839

Middle Eastern (MID)

AF:

0.390

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.253

AC:

13375

AN:

52808

Other (OTH)

AF:

0.296

AC:

442

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

790

1580

2371

3161

3951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.275

Hom.:

2013

Bravo

AF:

0.327

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.0

(source)

DANN

Benign

0.73

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over