chrX-11298569-C-A
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
Consequence
NM_001142.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AMELX | ENST00000380714.7 | c.166C>A | p.Pro56Thr | missense_variant | Exon 5 of 6 | 1 | NM_001142.2 | ENSP00000370090.3 | ||
ARHGAP6 | ENST00000337414.9 | c.589-43862G>T | intron_variant | Intron 1 of 12 | 1 | NM_013427.3 | ENSP00000338967.4 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
AMELX-related disorder Pathogenic:1
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
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at