chr4-70642685-T-TAG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_031889.3(ENAM):c.1259_1260insAG(p.Pro422ValfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,610,640 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_031889.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000292 AC: 72AN: 246350Hom.: 0 AF XY: 0.000322 AC XY: 43AN XY: 133524
GnomAD4 exome AF: 0.000250 AC: 365AN: 1458524Hom.: 0 Cov.: 34 AF XY: 0.000276 AC XY: 200AN XY: 725418
GnomAD4 genome AF: 0.000184 AC: 28AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74310
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This sequence change creates a premature translational stop signal (p.Pro422Valfs*27) in the ENAM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 721 amino acid(s) of the ENAM protein. This variant is present in population databases (rs587776588, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with amelogenesis imperfecta (PMID: 14684688, 16246937, 17125728, 19329462, 20439930). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4238). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Heterozygotes have been reported to have localized hypoplastic enamel pitting defects (Hart et al., 2003; Ozdemir et al., 2005; Pavlic et al., 2007); Frameshift variant predicted to result in protein truncation, as the last 721 amino acids are replaced with 26 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Hart et al., 2003); This variant is associated with the following publications: (PMID: 34426522, 19329462, 28694781, 21597265, 31589614, 31069529, 20439930, 17125728, 31478359, 14684688, 16246937) -
ENAM: PM3:Strong, PVS1:Strong, PM2 -
Amelogenesis imperfecta type 1C Pathogenic:2
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The ENAM variant (c.1259_1260insAG,p.Pro422Valfs*27) identified in this patient is a frameshift variant considered to be likely pathogenic (Hart et al. 2003, PMID: 14684688 ; Wright et al. 2011, PMID: 21597265) and not associated with the autosomal dominant amelogenesis imperfecta type 1B (MIM:104500). Carriers of this condition have been reported to have localized enamel defects: pitted or grooved teeth, or small and discolored teeth that are prone to premature wearing. -
ENAM-related disorder Pathogenic:1
The ENAM c.1259_1260insAG variant is predicted to result in a frameshift and premature protein termination (p.Pro422Valfs*27). This variant, also described as c.1258_1259insAG (p.P422fsX448) in the literature, has been reported in individuals with amelogenesis imperfecta (Hart et al. 2003. PubMed ID: 14684688; Pavlic et al. 2007. PubMed ID: 17125728; Wright et al. 2011. PubMed ID: 21597265; Zhang et al. 2019. PubMed ID: 31478359). It has been shown to be associated with phenotypic diversity, ranging from unaffected carrier parent (Family 2, Zhang et al. 2019. PubMed ID: 31478359), to localized hypoplastic enamel pitting as a dominant trait, and hypoplastic AI as a recessive trait (Family 1, Pavlic et al. 2007. PubMed ID: 17125728; Hart et al. 2003. PubMed ID: 14684688; Ozdemir et al. 2005. PubMed ID: 16246937). This variant is reported in 0.050% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ENAM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Amelogenesis imperfecta - hypoplastic autosomal dominant - local Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at