rs587776588

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.673

Publications

7 publications found

Variant links:

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]

ENAM Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 1B
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
amelogenesis imperfecta type 1C
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENAM links:

ENSG00000286848 (HGNC:58806):

ENSG00000286848 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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. Fraction of 0.633 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PP5

Variant 4-70642685-T-TAG is Pathogenic according to our data. Variant chr4-70642685-T-TAG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAM	NM_031889.3 link	c.1259_1260insAG	p.Pro422ValfsTer27	frameshift_variant	Exon 9 of 9	ENST00000396073.4	NP_114095.2
ENAM	NM_001368133.1 link	c.605_606insAG	p.Pro204ValfsTer27	frameshift_variant	Exon 2 of 2		NP_001355062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4 link	c.1259_1260insAG	p.Pro422ValfsTer27	frameshift_variant	Exon 9 of 9	1	NM_031889.3	ENSP00000379383.4
ENSG00000286848	ENST00000472903.5 link	n.99+4842_99+4843insAG		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000292

AC:

AN:

246350

AF XY:

0.000322

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000250

AC:

365

AN:

1458524

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

200

AN XY:

725418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33190

American (AMR)

AF:

0.00

AC:

AN:

44088

Ashkenazi Jewish (ASJ)

AF:

0.0000772

AC:

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000479

AC:

AN:

85594

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000269

AC:

299

AN:

1110826

Other (OTH)

AF:

0.0000831

AC:

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000624

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000423

Hom.:

Bravo

AF:

0.000170

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 21, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ENAM: PP1:Strong, PVS1:Strong, PM2, PS4:Moderate -

Amelogenesis imperfecta type 1C

Pathogenic:2

Jul 31, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

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. -

Mar 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Amelogenesis imperfecta - hypoplastic autosomal dominant - local;C2673923:Amelogenesis imperfecta type 1C

Pathogenic:1

Apr 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

ENAM-related disorder

Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Mar 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.67

Mutation Taster

=27/173

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over