ENAM

protein-coding

enamelin

Gene summary

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]

Previous symbols:

AIH2

MANE transcript

NM_031889.3

Inheritance

AD, SD, AR

ClinVar variants

P:21U:207B:48

Top phenotype

Amelogenesis imperfecta, type IB; Amelogenesis imperfecta, type IC

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr4:70,628,744-70,646,824

External References & Databases

Ensembl (ENSG00000132464)

Transcript & Mutation Effects

hg38 • Region Span ~18.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amelogenesis imperfecta type 1BDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007092

Submitter: Ambry Genetics

amelogenesis imperfecta type 1BSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0007092

Submitter: Ambry Genetics

amelogenesis imperfecta type 1STRONG

Inheritance Pattern: SD

Disease ID:MONDO:0015047

Submitter: PanelApp Australia

amelogenesis imperfecta type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015047

Submitter: Orphanet

amelogenesis imperfecta type 1BSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007092

Submitter: Labcorp Genetics (formerly Invitae)

amelogenesis imperfecta type 1CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008770

Submitter: Labcorp Genetics (formerly Invitae)

amelogenesis imperfecta type 1CLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008770

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Amelogenesis imperfecta, type IB; Amelogenesis imperfecta, type ICAD/AR

Manifestation: Dental

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11487571; 11978766; 14684688; 22243262

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ENAM variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 162

Amelogenesis imperfectaTotal: 55

not providedTotal: 44

not specifiedTotal: 20

ENAM-related disorderTotal: 16

Amelogenesis imperfecta - hypoplastic autosomal dominant - localTotal: 15

Amelogenesis imperfecta type 1CTotal: 6

ENAM-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031889.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	22 clinvar	3 clinvar	34
missense		1 clinvar	194 clinvar	20 clinvar	3 clinvar	218
nonsense	4 clinvar	3 clinvar	2 clinvar			9
start loss						0
frameshift	1 clinvar	8 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar	1 clinvar			5
Total	8	13	207	42	6	276

Highest pathogenic variant AF is 0.0002973952

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031889.3	RefSeq	NP_114095.2	8	MANE Select
ENST00000396073.4	Ensembl	ENSP00000379383.4	8	MANE Select
NM_001368133.1	RefSeq	NP_001355062.1	1	Standard
ENST00000472597.1	Ensembl	ENSP00000497682.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein phosphorylation
Post-translational protein modification
Metabolism of proteins
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

Biological Process

regulation of cell morphogenesis
biomineral tissue development
ameloblast differentiation
post-translational protein modification
cellular protein metabolic process

Molecular Function

protein binding
structural constituent of tooth enamel

Cellular Component

endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396073
Coding exons: 8
Length: 58073
Individuals with no LoFs: 125559
Homozygous LoFs: 0
Heterozygous LoFs: 188
Defined: 125747
p: 0.000748

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.456	618	587	1.05	0.0000295	7554
Missense (PolyPhen)		144	141.89	1.0149		2036
Synonymous	-1.58	235	206	1.14	0.0000103	2179
Loss of Function	2.41	26	43.1	0.604	0.00000198	558

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.0012	0.0012	notable
South Asian	0.00060	0.00059	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the mineralization and structural organization of enamel. Involved in the extension of enamel during the secretory stage of dental enamel formation. {ECO:0000250|UniProtKB:O97939}.;
Disease: DISEASE: Amelogenesis imperfecta 1B (AI1B) [MIM:104500]: An autosomal dominant defect of enamel formation. Clinical manifestations may be variable. Some cases present with generalized enamel hypoplasia resulting in small, smooth, yellow and widely spaced teeth (smooth hypoplastic AI). Others show horizontal rows of pits, grooves or a hypoplastic area in the enamel (local hypoplastic AI). {ECO:0000269|PubMed:11487571, ECO:0000269|PubMed:11978766, ECO:0000269|PubMed:20439930, ECO:0000269|PubMed:25789606}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amelogenesis imperfecta 1C (AI1C) [MIM:204650]: An autosomal recessive defect of dental enamel formation. Teeth show local hypoplastic and unmineralized enamel, and a yellow-brown discoloration. Enamel defects can be associated with facial and oral features including vertical dysgnathia and anterior openbite malocclusion. {ECO:0000269|PubMed:14684688, ECO:0000269|PubMed:20439930, ECO:0000269|PubMed:25789606}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.118

Intolerance Scores

LoFtool: 0.789
RVIS EVS: -0.08
RVIS percentile EVS: 47.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0891

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium