rs587776588
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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
Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
ENAM
NM_031889.3 frameshift
NM_031889.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.673
Genes affected
ENAM (HGNC:3344): (enamelin) Dental enamel forms the outer cap of teeth and is the hardest substance found in vertebrates. This gene encodes the largest protein in the enamel matrix of developing teeth. The protein is involved in the mineralization and structural organization of enamel. Defects in this gene result in amelogenesis imperfect type 1C.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-70642685-T-TAG is Pathogenic according to our data. Variant chr4-70642685-T-TAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ENAM | NM_031889.3 | c.1259_1260insAG | p.Pro422ValfsTer27 | frameshift_variant | 9/9 | ENST00000396073.4 | |
ENAM | NM_001368133.1 | c.605_606insAG | p.Pro204ValfsTer27 | frameshift_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ENAM | ENST00000396073.4 | c.1259_1260insAG | p.Pro422ValfsTer27 | frameshift_variant | 9/9 | 1 | NM_031889.3 | P1 | |
ENST00000472903.5 | n.99+4842_99+4843insAG | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000292 AC: 72AN: 246350Hom.: 0 AF XY: 0.000322 AC XY: 43AN XY: 133524
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GnomAD4 exome AF: 0.000250 AC: 365AN: 1458524Hom.: 0 Cov.: 34 AF XY: 0.000276 AC XY: 200AN XY: 725418
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 05, 2022 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | ENAM: PM3:Strong, PVS1:Strong, PM2 - |
Amelogenesis imperfecta type 1C Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2007 | - - |
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 31, 2014 | 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
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2024 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2007 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at