NM_001142.2:c.431delC

Variant names:

• chrX-11298832-GC-G
• rs387906489
• NM_001142.2:c.431delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001142.2(AMELX):​c.431delC​(p.Pro144HisfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,923 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AMELX NM_001142.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.0130
• 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 12 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-11298832-GC-G is Pathogenic according to our data. Variant chrX-11298832-GC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11139.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	NM_001142.2	MANE Select	c.431delC	p.Pro144HisfsTer31	frameshift	Exon 5 of 6	NP_001133.1	Q99217-1
	ARHGAP6	NM_013427.3	MANE Select	c.589-44126delG		intron	N/A	NP_038286.2	O43182-1
	AMELX	NM_182680.1		c.473delC	p.Pro158HisfsTer31	frameshift	Exon 6 of 7	NP_872621.1	Q99217-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMELX	ENST00000380714.7	TSL:1 MANE Select	c.431delC	p.Pro144HisfsTer31	frameshift	Exon 5 of 6	ENSP00000370090.3	Q99217-1
	AMELX	ENST00000380712.7	TSL:1	c.473delC	p.Pro158HisfsTer31	frameshift	Exon 6 of 7	ENSP00000370088.3	Q99217-3
	ARHGAP6	ENST00000337414.9	TSL:1 MANE Select	c.589-44126delG		intron	N/A	ENSP00000338967.4	O43182-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097923 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363319

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30189

South Asian (SAS) AF: 0.00 AC: 0 AN: 54098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841996

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Amelogenesis imperfecta type 1E (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.013
Mutation Taster		=39/161	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906489;

hg19: chrX-11316952;