Genetic Variant ARHGAP6:c.589-11_589-10dupTT (chrX-11254716-C-CAA) – 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.589-11_589-10dupTT 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 0.025 ( 8 hom., 50 hem., cov: 19)

Exomes 𝑓: 0.0051 ( 2 hom. 11 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 nfe. GnomAd4 allele frequency = 0.0253 (892/35239) while in subpopulation NFE AF = 0.0402 (732/18216). AF 95% confidence interval is 0.0378. There are 8 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 gene

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_589-10dupTT	intron	N/A	NP_038286.2	O43182-1
ARHGAP6	NM_001287242.2		c.49-11_49-10dupTT	intron	N/A	NP_001274171.1
ARHGAP6	NM_013423.3		c.-21-11_-21-10dupTT	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.589-10_589-9insTT	intron	N/A	ENSP00000338967.4	O43182-1
ARHGAP6	ENST00000303025.10	TSL:1	c.-21-10_-21-9insTT	intron	N/A	ENSP00000302312.6	O43182-4
ARHGAP6	ENST00000380736.5	TSL:1	c.-21-10_-21-9insTT	intron	N/A	ENSP00000370112.1	O43182-4

Frequencies

GnomAD3 genomes

AF:

0.0254

AC:

894

AN:

35243

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00607

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0116

Gnomad EAS

AF:

0.00452

Gnomad SAS

AF:

0.0392

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.0294

Gnomad NFE

AF:

0.0403

Gnomad OTH

AF:

0.0197

GnomAD4 exome

AF:

0.00511

AC:

4193

AN:

820541

Hom.:

Cov.:

AF XY:

0.0000466

AC XY:

AN XY:

235901

show subpopulations

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

African (AFR)

AF:

0.00240

AC:

AN:

18764

American (AMR)

AF:

0.00634

AC:

AN:

10256

Ashkenazi Jewish (ASJ)

AF:

0.00190

AC:

AN:

11054

East Asian (EAS)

AF:

0.00124

AC:

AN:

21754

South Asian (SAS)

AF:

0.00781

AC:

149

AN:

19081

European-Finnish (FIN)

AF:

0.00210

AC:

AN:

21861

Middle Eastern (MID)

AF:

0.00202

AC:

AN:

1983

European-Non Finnish (NFE)

AF:

0.00542

AC:

3696

AN:

681945

Other (OTH)

AF:

0.00414

AC:

140

AN:

33843

⚠️ 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: 0.272

Heterozygous variant carriers

440

879

1319

1758

2198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

174

348

522

696

870

<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:

0.0253

AC:

892

AN:

35239

Hom.:

Cov.:

AF XY:

0.00852

AC XY:

AN XY:

5869

show subpopulations

African (AFR)

AF:

0.00606

AC:

AN:

9242

American (AMR)

AF:

0.0116

AC:

AN:

3279

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

AN:

952

East Asian (EAS)

AF:

0.00455

AC:

AN:

1099

South Asian (SAS)

AF:

0.0396

AC:

AN:

631

European-Finnish (FIN)

AF:

0.0127

AC:

AN:

1099

Middle Eastern (MID)

AF:

0.0323

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0402

AC:

732

AN:

18216

Other (OTH)

AF:

0.0194

AC:

AN:

465

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

102

136

170

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:

0.00677

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

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-11254716-CAAAAAAAAAAAA-CAAAAAAAAAAAAAA

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