4-70631694-C-A

Variant names:

• chr4-70631694-C-A
• NM_031889.3:c.79C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031889.3(ENAM):​c.79C>A​(p.Leu27Ile) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L27P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENAM NM_031889.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0430
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3503976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAM	NM_031889.3	c.79C>A	p.Leu27Ile	missense_variant	Exon 3 of 9	ENST00000396073.4	NP_114095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4	c.79C>A	p.Leu27Ile	missense_variant	Exon 3 of 9	1	NM_031889.3	ENSP00000379383.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amelogenesis imperfecta - hypoplastic autosomal dominant - local Uncertain:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with amelogenesis imperfecta, type IC (MIM#204650), and amelogenesis imperfecta, type IB (MIM#104500). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive inheritance is associated with a more severe phenotype (PMID: 33864320). (I) 0112 - The condition associated with this gene has incomplete penetrance. Unaffected carriers of pathogenic variants have been described (PMID: 33864320). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability of disease severity has been described (PMID: 12828988). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Benign	0.027
Eigen_PC	Benign	-0.0064
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.043
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.12
Sift	Benign	0.098	T
Sift4G	Uncertain	0.043	D
Polyphen		0.98	D
Vest4		0.54
MutPred		0.17		Loss of catalytic residue at L27 (P = 0.1002);
MVP		0.45
MPC		0.034
ClinPred		0.50	D
GERP RS		3.0
Varity_R		0.048
gMVP		0.11
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr4-71497411; COSMIC: COSV68535365;