Genetic Variant ARHGAP6:c.589-14_589-10delTTTTT (chrX-11254716-CAAAAA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_013427.3(ARHGAP6):c.589-14_589-10delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 858,010 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 9 hem., cov: 19)

Exomes 𝑓: 0.0013 ( 0 hom. 8 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3 link	c.589-14_589-10delTTTTT		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.589-14_589-10delTTTTT		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

AN:

35322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00304

Gnomad ASJ

AF:

0.0189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.00438

GnomAD2 exomes

AF:

0.0171

AC:

257

AN:

15013

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0297

Gnomad EAS exome

AF:

0.0177

Gnomad FIN exome

AF:

0.00361

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0260

GnomAD4 exome

AF:

0.00130

AC:

1071

AN:

822692

Hom.:

AF XY:

0.0000338

AC XY:

AN XY:

236940

show subpopulations

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

African (AFR)

AF:

0.00193

AC:

AN:

18655

American (AMR)

AF:

0.00566

AC:

AN:

10074

Ashkenazi Jewish (ASJ)

AF:

0.00688

AC:

AN:

10905

East Asian (EAS)

AF:

0.00181

AC:

AN:

21503

South Asian (SAS)

AF:

0.00288

AC:

AN:

19117

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

21658

Middle Eastern (MID)

AF:

0.00404

AC:

AN:

1982

European-Non Finnish (NFE)

AF:

0.00101

AC:

690

AN:

684881

Other (OTH)

AF:

0.00203

AC:

AN:

33917

⚠️ 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: 0.274

Heterozygous variant carriers

112

223

335

446

558

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:

0.00108

AC:

AN:

35318

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

AN XY:

5878

show subpopulations

African (AFR)

AF:

0.000108

AC:

AN:

9258

American (AMR)

AF:

0.00304

AC:

AN:

3290

Ashkenazi Jewish (ASJ)

AF:

0.0189

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:

0.00

AC:

AN:

1101

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

18258

Other (OTH)

AF:

0.00429

AC:

AN:

466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.00

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

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

Publications

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X-11254716-CAAAAAAAAAAAA-CAAAAAAA

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