rs5934997

Variant names:

• chrX-11295613-T-C
• rs5934997
• NM_013427.3:c.589-40906A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013427.3(ARHGAP6):​c.589-40906A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 109,722 control chromosomes in the GnomAD database, including 5,216 homozygotes. There are 9,857 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (5216 hom., 9857 hem., cov: 21)
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP6	NM_013427.3	MANE Select	c.589-40906A>G		intron	N/A	NP_038286.2
	AMELX	NM_001142.2	MANE Select	c.54+771T>C		intron	N/A	NP_001133.1
	ARHGAP6	NM_001287242.2		c.49-40906A>G		intron	N/A	NP_001274171.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-40906A>G		intron	N/A	ENSP00000338967.4
	AMELX	ENST00000380714.7	TSL:1 MANE Select	c.54+771T>C		intron	N/A	ENSP00000370090.3
	ARHGAP6	ENST00000380736.5	TSL:1	c.-21-40906A>G		intron	N/A	ENSP00000370112.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 35607 AN: 109668 Hom.: 5212 Cov.: 21

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.374

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.300

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

GnomAD4 genome AF: 0.325 AC: 35655 AN: 109722 Hom.: 5216 Cov.: 21 AF XY: 0.308 AC XY: 9857 AN XY: 32046

African (AFR) AF: 0.557 AC: 16703 AN: 29985

American (AMR) AF: 0.192 AC: 1985 AN: 10333

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 805 AN: 2615

East Asian (EAS) AF: 0.0238 AC: 83 AN: 3489

South Asian (SAS) AF: 0.222 AC: 570 AN: 2563

European-Finnish (FIN) AF: 0.289 AC: 1651 AN: 5705

Middle Eastern (MID) AF: 0.395 AC: 85 AN: 215

European-Non Finnish (NFE) AF: 0.253 AC: 13308 AN: 52644

Other (OTH) AF: 0.296 AC: 441 AN: 1489

Alfa AF: 0.310 Hom.: 2365

Bravo AF: 0.327

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.79
PhyloP100		0.18
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: rs5934997; hg19: chrX-11313733;