rs104894736
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_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
NM_001142.2 missense
Scores
7
8
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | P1 | |
ARHGAP6 | ENST00000337414.9 | c.589-43862G>T | intron_variant | 1 | NM_013427.3 | ENSP00000338967 | P2 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
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. - |
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) - |
Amelogenesis imperfecta type 1E Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M;.
MutationTaster
Benign
A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;D
Vest4
MutPred
0.78
.;Loss of disorder (P = 0.0995);.;
MVP
MPC
0.88
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at