rs5979395

Variant names:

• chrX-11296514-G-A
• rs5979395
• NM_013427.3:c.589-41807C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013427.3(ARHGAP6):​c.589-41807C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 110,964 control chromosomes in the GnomAD database, including 1,802 homozygotes. There are 6,491 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (1802 hom., 6491 hem., cov: 22)
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47
• Publications: 7 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]

AMELX (HGNC:461): (amelogenin X-linked) This gene encodes a member of the amelogenin family of extracellular matrix proteins. Amelogenins are involved in biomineralization during tooth enamel development. Mutations in this gene cause X-linked amelogenesis imperfecta. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

AMELX Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 1E

  Inheritance: XL Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-11296514-G-A is Benign according to our data. Variant chrX-11296514-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276391.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3	c.589-41807C>T		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2
AMELX	NM_001142.2	c.55-265G>A		intron_variant	Intron 2 of 5	ENST00000380714.7	NP_001133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP6	ENST00000337414.9	c.589-41807C>T		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4
AMELX	ENST00000380714.7	c.55-265G>A		intron_variant	Intron 2 of 5	1	NM_001142.2	ENSP00000370090.3

Frequencies

GnomAD3 genomes AF: 0.205 AC: 22763 AN: 110912 Hom.: 1806 Cov.: 22

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0453

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.0184

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.191

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.205 AC: 22783 AN: 110964 Hom.: 1802 Cov.: 22 AF XY: 0.195 AC XY: 6491 AN XY: 33230

African (AFR) AF: 0.208 AC: 6357 AN: 30517

American (AMR) AF: 0.133 AC: 1404 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 649 AN: 2634

East Asian (EAS) AF: 0.0187 AC: 66 AN: 3529

South Asian (SAS) AF: 0.157 AC: 413 AN: 2638

European-Finnish (FIN) AF: 0.284 AC: 1669 AN: 5872

Middle Eastern (MID) AF: 0.316 AC: 67 AN: 212

European-Non Finnish (NFE) AF: 0.224 AC: 11842 AN: 52834

Other (OTH) AF: 0.188 AC: 285 AN: 1512

Alfa AF: 0.215 Hom.: 17775

Bravo AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.3
DANN	Benign	0.38
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs5979395; hg19: chrX-11314634;