rs104894736

Positions:

• chrX-11298569-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001142.2(AMELX):​c.166C>A​(p.Pro56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: AMELX NM_001142.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.25

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]

ARHGAP6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-11298569-C-A is Pathogenic according to our data. Variant chrX-11298569-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMELX	NM_001142.2	c.166C>A	p.Pro56Thr	missense_variant	5/6	ENST00000380714.7	NP_001133.1
ARHGAP6	NM_013427.3	c.589-43862G>T		intron_variant		ENST00000337414.9	NP_038286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMELX	ENST00000380714.7	c.166C>A	p.Pro56Thr	missense_variant	5/6	1	NM_001142.2	ENSP00000370090.3
ARHGAP6	ENST00000337414.9	c.589-43862G>T		intron_variant		1	NM_013427.3	ENSP00000338967.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

AMELX-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The AMELX c.208C>A variant is predicted to result in the amino acid substitution p.Pro70Thr. This variant, alternatively referred to as P41T in the literature and c.166C>A (p.Pro56Thr) in ClinVar, has been reported to segregate in multiple families with amelogenesis imperfecta (AI) (Collier et al. 1997. PubMed ID: 9188994; Ravassipour et al. 2000. PubMed ID: 11005731; Hart et al. 2000. PubMed ID: 10669095; Chan et al. 2011. PubMed ID: 22243262). Affected individuals present with a distinct and consistent hypomaturation form of AI. Functional studies demonstrate protein instability and decreased binding affinity for amelogenin (Tanimoto et al. 2008. PubMed ID: 18434575; Lakshminarayanan et al. 2010. PubMed ID: 20929860). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Amelogenesis imperfecta type 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 2024

Published functional studies demonstrate a damaging effect causing decreased degradation of amelogenin by MMP20 resulting in altered mineralization (PMID: 21081224, 18434575, 31239344); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18390542, 11922869, 22243262, 20929860, 18434575, 17384027, 20923441, 16674655, 10669095, 11005731, 15892947, 21127961, 12952177, 16838342, 21597265, 9188994, 16674656, 31239344, 21081224) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.78		.;Loss of disorder (P = 0.0995);.;
MVP		1.0
MPC		0.88
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894736; hg19: chrX-11316689;