Genetic Variant ARHGAP6:c.589-11_589-10delTT (chrX-11254716-CAA-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013427.3(ARHGAP6):c.589-11_589-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 725,635 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.051 ( 0 hom. 0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the AMR (0.0697) population. However there is too low homozygotes in high coverage region: (expected more than 429, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013427.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGAP6	NM_013427.3	MANE Select	c.589-11_589-10delTT	intron	N/A	NP_038286.2	O43182-1
ARHGAP6	NM_001287242.2		c.49-11_49-10delTT	intron	N/A	NP_001274171.1
ARHGAP6	NM_013423.3		c.-21-11_-21-10delTT	intron	N/A	NP_038267.1	O43182-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-11_589-10delTT	intron	N/A	ENSP00000338967.4	O43182-1
ARHGAP6	ENST00000303025.10	TSL:1	c.-21-11_-21-10delTT	intron	N/A	ENSP00000302312.6	O43182-4
ARHGAP6	ENST00000380736.5	TSL:1	c.-21-11_-21-10delTT	intron	N/A	ENSP00000370112.1	O43182-4

Frequencies

GnomAD3 genomes

AF:

0.000481

AC:

AN:

35310

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000608

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00914

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.108

AC:

1624

AN:

15013

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.126

Gnomad OTH exome

AF:

0.125

GnomAD4 exome

AF:

0.0511

AC:

35298

AN:

690329

Hom.:

AF XY:

0.00

AC XY:

AN XY:

181603

show subpopulations

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

African (AFR)

AF:

0.0621

AC:

974

AN:

15692

American (AMR)

AF:

0.0743

AC:

660

AN:

8877

Ashkenazi Jewish (ASJ)

AF:

0.0572

AC:

512

AN:

8957

East Asian (EAS)

AF:

0.0675

AC:

1173

AN:

17382

South Asian (SAS)

AF:

0.0443

AC:

728

AN:

16428

European-Finnish (FIN)

AF:

0.0560

AC:

1038

AN:

18540

Middle Eastern (MID)

AF:

0.0527

AC:

AN:

1669

European-Non Finnish (NFE)

AF:

0.0497

AC:

28544

AN:

574525

Other (OTH)

AF:

0.0559

AC:

1581

AN:

28259

⚠️ 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: 0.267

Heterozygous variant carriers

3948

7897

11845

15794

19742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1138

2276

3414

4552

5690

<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:

0.000482

AC:

AN:

35306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

5876

show subpopulations

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

African (AFR)

AF:

0.000216

AC:

AN:

9258

American (AMR)

AF:

0.000608

AC:

AN:

3287

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

954

East Asian (EAS)

AF:

0.00

AC:

AN:

1101

South Asian (SAS)

AF:

0.00

AC:

AN:

634

European-Finnish (FIN)

AF:

0.00914

AC:

AN:

1094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

18256

Other (OTH)

AF:

0.00

AC:

AN:

466

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.293

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00677

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.085

Mutation Taster

=100/0

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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X-11254716-CAAAAAAAAAAAA-CAAAAAAAAAA

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