rs387906487

chrX-11298242-AC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001142.2(AMELX):c.113del(p.Pro38LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,097,814 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: AMELX NM_001142.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.71

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

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-11298242-AC-A is Pathogenic according to our data. Variant chrX-11298242-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 11137.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMELX	NM_001142.2	c.113del	p.Pro38LeufsTer2	frameshift_variant	4/6	ENST00000380714.7
ARHGAP6	NM_013427.3	c.589-43536del		intron_variant		ENST00000337414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMELX	ENST00000380714.7	c.113del	p.Pro38LeufsTer2	frameshift_variant	4/6	1	NM_001142.2	P1
ARHGAP6	ENST00000337414.9	c.589-43536del		intron_variant		1	NM_013427.3	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097814 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta type 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387906487; hg19: chrX-11316362;