ENAM p.Phe576Leu

Variant names:

• chr4-70643154-T-A
• NM_031889.3:c.1728T>A
• ENAM p.Phe576Leu

Your query was ambiguous. Multiple possible variants found:

• chr4-70643154-T-A
• chr4-70643154-T-G
• chr4-70643152-T-C
• chr4-70643152-TTT-CTC
• chr4-70643152-TTT-CTA
• chr4-70643152-TTT-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031889.3(ENAM):​c.1728T>A​(p.Phe576Leu) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENAM NM_031889.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.265
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ENSG00000286848 (HGNC:58806):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13613358).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031889.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAM	NM_031889.3	MANE Select	c.1728T>A	p.Phe576Leu	missense	Exon 9 of 9	NP_114095.2	Q9NRM1
	ENAM	NM_001368133.1		c.1074T>A	p.Phe358Leu	missense	Exon 2 of 2	NP_001355062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAM	ENST00000396073.4	TSL:1 MANE Select	c.1728T>A	p.Phe576Leu	missense	Exon 9 of 9	ENSP00000379383.4	Q9NRM1
	ENSG00000286848	ENST00000472903.5	TSL:5	n.99+5311T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.27
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.086
Sift	Benign	0.16	T
Sift4G	Benign	0.53	T
Varity_R		0.20
gMVP		0.28
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-71508871;