X-11298898-GC-G

Variant names:

• chrX-11298898-GC-G
• rs387906490
• NM_001142.2:c.499delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001142.2(AMELX):​c.499delC​(p.Leu167CysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AMELX NM_001142.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.61
• Publications: 4 publications found

Genes affected

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]

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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11298898-GC-G is Pathogenic according to our data. Variant chrX-11298898-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 11143.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142.2. 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
	AMELX	NM_001142.2	MANE Select	c.499delC	p.Leu167CysfsTer8	frameshift	Exon 5 of 6	NP_001133.1
	ARHGAP6	NM_013427.3	MANE Select	c.589-44192delG		intron	N/A	NP_038286.2
	AMELX	NM_182680.1		c.541delC	p.Leu181CysfsTer8	frameshift	Exon 6 of 7	NP_872621.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	ENST00000380714.7	TSL:1 MANE Select	c.499delC	p.Leu167CysfsTer8	frameshift	Exon 5 of 6	ENSP00000370090.3
	AMELX	ENST00000380712.7	TSL:1	c.541delC	p.Leu181CysfsTer8	frameshift	Exon 6 of 7	ENSP00000370088.3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-44192delG		intron	N/A	ENSP00000338967.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta type 1E Pathogenic:1

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs387906490; hg19: chrX-11317018;