X-11295828-T-C

Variant names:

• chrX-11295828-T-C
• rs17878486
• NM_013427.3:c.589-41121A>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.589-41121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 111,107 control chromosomes in the GnomAD database, including 1,689 homozygotes. There are 5,521 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 0.17 (1689 hom., 5521 hem., cov: 22)
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 22 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3	c.589-41121A>G		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2
AMELX	NM_001142.2	c.55-951T>C		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.589-41121A>G		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4
AMELX	ENST00000380714.7	c.55-951T>C		intron_variant	Intron 2 of 5	1	NM_001142.2	ENSP00000370090.3

Frequencies

GnomAD3 genomes AF: 0.173 AC: 19190 AN: 111049 Hom.: 1690 Cov.: 22

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.173 AC: 19184 AN: 111107 Hom.: 1689 Cov.: 22 AF XY: 0.166 AC XY: 5521 AN XY: 33333

African (AFR) AF: 0.0347 AC: 1063 AN: 30671

American (AMR) AF: 0.129 AC: 1350 AN: 10474

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 645 AN: 2628

East Asian (EAS) AF: 0.00141 AC: 5 AN: 3547

South Asian (SAS) AF: 0.0830 AC: 217 AN: 2616

European-Finnish (FIN) AF: 0.248 AC: 1455 AN: 5874

Middle Eastern (MID) AF: 0.147 AC: 32 AN: 217

European-Non Finnish (NFE) AF: 0.263 AC: 13903 AN: 52895

Other (OTH) AF: 0.165 AC: 250 AN: 1511

Alfa AF: 0.0901 Hom.: 831

Bravo AF: 0.159

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.19
DANN	Benign	0.60
PhyloP100		-1.4
Mutation Taster		=99/1	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: rs17878486; hg19: chrX-11313948;