Genetic Variant ARHGAP6:c.589-10delT (chrX-11254716-CA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_013427.3(ARHGAP6):c.589-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 1 hom., 31 hem., cov: 19)

Exomes 𝑓: 0.20 ( 0 hom. 14 hem. )

Consequence

ARHGAP6
NM_013427.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0166 (585/35302) while in subpopulation AFR AF = 0.048 (444/9253). AF 95% confidence interval is 0.0443. There are 1 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3 link	c.589-10delT		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP6	ENST00000337414.9 link	c.589-10delT		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

584

AN:

35306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0479

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00181

Gnomad SAS

AF:

0.00312

Gnomad FIN

AF:

0.0466

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00257

Gnomad OTH

AF:

0.0109

GnomAD2 exomes

AF:

0.120

AC:

1803

AN:

15013

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.163

Gnomad AMR exome

AF:

0.150

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.0158

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.204

AC:

138923

AN:

679391

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

123285

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.211

AC:

3352

AN:

15854

American (AMR)

AF:

0.140

AC:

1284

AN:

9184

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

1569

AN:

9147

East Asian (EAS)

AF:

0.180

AC:

3342

AN:

18602

South Asian (SAS)

AF:

0.157

AC:

2444

AN:

15602

European-Finnish (FIN)

AF:

0.133

AC:

2597

AN:

19502

Middle Eastern (MID)

AF:

0.165

AC:

261

AN:

1586

European-Non Finnish (NFE)

AF:

0.211

AC:

118298

AN:

561470

Other (OTH)

AF:

0.203

AC:

5776

AN:

28444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.296

Heterozygous variant carriers

10582

21164

31745

42327

52909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5520

11040

16560

22080

27600

<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:

0.0166

AC:

585

AN:

35302

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

AN XY:

5866

show subpopulations

African (AFR)

AF:

0.0480

AC:

444

AN:

9253

American (AMR)

AF:

0.0103

AC:

AN:

3290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

954

East Asian (EAS)

AF:

0.00182

AC:

AN:

1101

South Asian (SAS)

AF:

0.00315

AC:

AN:

634

European-Finnish (FIN)

AF:

0.0466

AC:

AN:

1094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00257

AC:

AN:

18254

Other (OTH)

AF:

0.0107

AC:

AN:

466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

111

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:

0.0119

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.085

Mutation Taster

=100/0

polymorphism

(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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X-11254716-CAAAAAAAAAAAA-CAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over