rs2609428

chr4-70643152-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031889.3(ENAM):c.1726T>C(p.Phe576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,613,944 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (366 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (358 hom.)
• Consequence: ENAM NM_031889.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.900

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016252697).
• BP6: Variant 4-70643152-T-C is Benign according to our data. Variant chr4-70643152-T-C is described in ClinVar as [Benign]. Clinvar id is 349499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENAM	NM_031889.3	c.1726T>C	p.Phe576Leu	missense_variant	9/9	ENST00000396073.4
ENAM	NM_001368133.1	c.1072T>C	p.Phe358Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENAM	ENST00000396073.4	c.1726T>C	p.Phe576Leu	missense_variant	9/9	1	NM_031889.3	P1
	ENST00000472903.5	n.99+5309T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0387 AC: 5878 AN: 151992 Hom.: 363 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0126 AC: 3153 AN: 251060 Hom.: 149 AF XY: 0.0100 AC XY: 1361 AN XY: 135782

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00268

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00593 AC: 8665 AN: 1461834 Hom.: 358 Cov.: 33 AF XY: 0.00544 AC XY: 3956 AN XY: 727214

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0388 AC: 5895 AN: 152110 Hom.: 366 Cov.: 31 AF XY: 0.0378 AC XY: 2812 AN XY: 74374

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0101 Hom.: 112

Bravo AF: 0.0448

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.120 AC: 528

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.0139 AC: 1690

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00385

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Amelogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.031
Sift	Benign	0.16	T
Sift4G	Benign	0.53	T
Polyphen		0.090	B
Vest4		0.069
MutPred		0.066		Loss of glycosylation at S573 (P = 0.032);
MPC		0.025
ClinPred		0.0086	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs2609428; hg19: chr4-71508869;