chr4-70643152-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/21 in silico tools predict 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.900

Publications

14 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:):

ENSG00000286848 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar as Benign. Clinvar id is 349499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-70643152-T-C is described in CliVar as Benign. Clinvar id is 349499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-70643152-T-C is described in CliVar 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 rank	MANE	Protein	UniProt
ENAM	NM_031889.3 link	c.1726T>C	p.Phe576Leu	missense_variant	Exon 9 of 9	ENST00000396073.4	NP_114095.2	Q9NRM1
ENAM	NM_001368133.1 link	c.1072T>C	p.Phe358Leu	missense_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.1726T>C	p.Phe576Leu	missense_variant	Exon 9 of 9	1	NM_031889.3	ENSP00000379383.4		Q9NRM1
ENSG00000286848	ENST00000472903.5 link	n.99+5309T>C		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0387

AC:

5878

AN:

151992

Hom.:

363

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0126

AC:

3153

AN:

251060

AF XY:

0.0100

show subpopulations

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 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.:

AF XY:

0.00544

AC XY:

3956

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.134

AC:

4486

AN:

33478

American (AMR)

AF:

0.0155

AC:

691

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

426

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000777

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.0288

AC:

166

AN:

5768

European-Non Finnish (NFE)

AF:

0.00184

AC:

2050

AN:

1111990

Other (OTH)

AF:

0.0127

AC:

769

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

516

1031

1547

2062

2578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.0388

AC:

5895

AN:

152110

Hom.:

366

Cov.:

AF XY:

0.0378

AC XY:

2812

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.123

AC:

5104

AN:

41462

American (AMR)

AF:

0.0310

AC:

474

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

67998

Other (OTH)

AF:

0.0374

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

252

504

755

1007

1259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0157

Hom.:

300

Bravo

AF:

0.0448

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.120

AC:

528

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.0139

AC:

1690

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00385

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Amelogenesis imperfecta

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

0.90

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.031

Sift

Benign

0.16

Sift4G

Benign

0.53

Polyphen

0.090

Vest4

0.069

MutPred

0.066

Loss of glycosylation at S573 (P = 0.032);

MPC

0.025

ClinPred

0.0086

GERP RS

3.5

Varity_R

0.22

gMVP

0.28

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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