X-11294907-T-C

Variant names:

• chrX-11294907-T-C
• rs946252
• NM_013427.3:c.589-40200A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_013427.3(ARHGAP6):​c.589-40200A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (21299 hom., 23745 hem., cov: 23)
  • Exomes 𝑓: 0.69 (168091 hom. 222518 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARHGAP6 NM_013427.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.18
• Publications: 34 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=-0.93).
• BP6: Variant X-11294907-T-C is Benign according to our data. Variant chrX-11294907-T-C is described in ClinVar as Benign. ClinVar VariationId is 1281204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP6	NM_013427.3	c.589-40200A>G		intron_variant	Intron 1 of 12	ENST00000337414.9	NP_038286.2
AMELX	NM_001142.2	c.54+65T>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.589-40200A>G		intron_variant	Intron 1 of 12	1	NM_013427.3	ENSP00000338967.4
AMELX	ENST00000380714.7	c.54+65T>C		intron_variant	Intron 2 of 5	1	NM_001142.2	ENSP00000370090.3

Frequencies

GnomAD3 genomes AF: 0.732 AC: 80836 AN: 110443 Hom.: 21296 Cov.: 23

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.727

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.688 AC: 710833 AN: 1033278 Hom.: 168091 AF XY: 0.696 AC XY: 222518 AN XY: 319508

African (AFR) AF: 0.859 AC: 21568 AN: 25119

American (AMR) AF: 0.839 AC: 29454 AN: 35090

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 12595 AN: 18980

East Asian (EAS) AF: 0.616 AC: 18440 AN: 29921

South Asian (SAS) AF: 0.571 AC: 30035 AN: 52607

European-Finnish (FIN) AF: 0.669 AC: 27087 AN: 40472

Middle Eastern (MID) AF: 0.712 AC: 2835 AN: 3981

European-Non Finnish (NFE) AF: 0.688 AC: 538920 AN: 783170

Other (OTH) AF: 0.680 AC: 29899 AN: 43938

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.732 AC: 80890 AN: 110505 Hom.: 21299 Cov.: 23 AF XY: 0.725 AC XY: 23745 AN XY: 32743

African (AFR) AF: 0.846 AC: 25672 AN: 30349

American (AMR) AF: 0.800 AC: 8372 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 1745 AN: 2645

East Asian (EAS) AF: 0.566 AC: 1966 AN: 3473

South Asian (SAS) AF: 0.532 AC: 1373 AN: 2579

European-Finnish (FIN) AF: 0.670 AC: 3902 AN: 5824

Middle Eastern (MID) AF: 0.757 AC: 162 AN: 214

European-Non Finnish (NFE) AF: 0.687 AC: 36264 AN: 52778

Other (OTH) AF: 0.721 AC: 1084 AN: 1504

Alfa AF: 0.691 Hom.: 37895

Bravo AF: 0.750

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

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	-0.93
CADD	Benign	1.0
DANN	Benign	0.56
PhyloP100		-1.2
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: rs946252; hg19: chrX-11313027; COSMIC: COSV61625132; COSMIC: COSV61625132;