X-11254716-CAAAAAAAAAAAA-CAAAAAAAAA

Variant names:

• chrX-11254716-CAAA-C
• rs751080433
• NM_013427.3:c.589-12_589-10delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_013427.3(ARHGAP6):​c.589-12_589-10delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 809,472 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.011 (0 hom. 0 hem.)
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 0 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0257) population. However there is too low homozygotes in high coverage region: (expected more than 21, got 0).
• BP6: Variant X-11254716-CAAA-C is Benign according to our data. Variant chrX-11254716-CAAA-C is described in ClinVar as Benign. ClinVar VariationId is 402392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 6 AN: 35319 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000304

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0613 AC: 920 AN: 15013 AF XY: 0.00

Gnomad AFR exome AF: 0.0571

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.0546

Gnomad FIN exome AF: 0.00902

Gnomad NFE exome AF: 0.0795

Gnomad OTH exome AF: 0.0442

GnomAD4 exome AF: 0.0108 AC: 8331 AN: 774153 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 217783

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

African (AFR) AF: 0.0146 AC: 256 AN: 17524

American (AMR) AF: 0.0285 AC: 272 AN: 9534

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 152 AN: 10151

East Asian (EAS) AF: 0.0139 AC: 276 AN: 19824

South Asian (SAS) AF: 0.0151 AC: 273 AN: 18033

European-Finnish (FIN) AF: 0.0146 AC: 297 AN: 20275

Middle Eastern (MID) AF: 0.0127 AC: 23 AN: 1818

European-Non Finnish (NFE) AF: 0.00988 AC: 6377 AN: 645151

Other (OTH) AF: 0.0127 AC: 405 AN: 31843

⚠️ 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 AF: 0.000170 AC: 6 AN: 35319 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 5875

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

African (AFR) AF: 0.000216 AC: 2 AN: 9244

American (AMR) AF: 0.000304 AC: 1 AN: 3291

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1108

South Asian (SAS) AF: 0.00 AC: 0 AN: 641

European-Finnish (FIN) AF: 0.00272 AC: 3 AN: 1102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18260

Other (OTH) AF: 0.00 AC: 0 AN: 457

⚠️ 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.

Alfa AF: 0.00284 Hom.: 45

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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)		0.0		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;