X-11254716-CAAAAAAAAAAAA-CAAAAAAAA

Variant names:

• chrX-11254716-CAAAA-C
• rs751080433
• NM_013427.3:c.589-13_589-10delTTTT

Variant summary

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

The NM_013427.3(ARHGAP6):​c.589-13_589-10delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 806,645 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 0.0 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0032 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0111) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3	c.589-13_589-10delTTTT		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	c.589-13_589-10delTTTT		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 35318 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0305 AC: 458 AN: 15013 AF XY: 0.00

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0297

Gnomad EAS exome AF: 0.0246

Gnomad FIN exome AF: 0.00721

Gnomad NFE exome AF: 0.0386

Gnomad OTH exome AF: 0.0286

GnomAD4 exome AF: 0.00319 AC: 2571 AN: 806645 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 230563

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

African (AFR) AF: 0.00452 AC: 83 AN: 18347

American (AMR) AF: 0.0129 AC: 128 AN: 9937

Ashkenazi Jewish (ASJ) AF: 0.00384 AC: 41 AN: 10668

East Asian (EAS) AF: 0.00400 AC: 84 AN: 20978

South Asian (SAS) AF: 0.00538 AC: 101 AN: 18767

European-Finnish (FIN) AF: 0.00558 AC: 118 AN: 21141

Middle Eastern (MID) AF: 0.00311 AC: 6 AN: 1930

European-Non Finnish (NFE) AF: 0.00282 AC: 1896 AN: 671709

Other (OTH) AF: 0.00344 AC: 114 AN: 33168

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 35314 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 5878

African (AFR) AF: 0.00 AC: 0 AN: 9260

American (AMR) AF: 0.00 AC: 0 AN: 3290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 954

East Asian (EAS) AF: 0.00 AC: 0 AN: 1101

South Asian (SAS) AF: 0.00 AC: 0 AN: 634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 62

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18255

Other (OTH) AF: 0.00 AC: 0 AN: 466

Alfa AF: 0.00204 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.085
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs751080433; hg19: chrX-11272836;