rs7671281

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1943T>C(p.Ile648Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 1,613,738 control chromosomes in the GnomAD database, including 9,962 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 4507 hom., cov: 31)

Exomes 𝑓: 0.054 ( 5455 hom. )

Consequence

ENAM
NM_031889.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.714

Publications

32 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: SD, AD 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:58806):

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=6.051093E-5).

BP6

Variant 4-70643369-T-C is Benign according to our data. Variant chr4-70643369-T-C is described in ClinVar as Benign. ClinVar VariationId is 261984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

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.1943T>C	p.Ile648Thr	missense	Exon 9 of 9	NP_114095.2	Q9NRM1
	ENAM	NM_001368133.1		c.1289T>C	p.Ile430Thr	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.1943T>C	p.Ile648Thr	missense	Exon 9 of 9	ENSP00000379383.4	Q9NRM1
	ENSG00000286848	ENST00000472903.5	TSL:5	n.99+5526T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24529

AN:

151924

Hom.:

4479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.451

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0830

Gnomad EAS

AF:

0.0198

Gnomad SAS

AF:

0.0614

Gnomad FIN

AF:

0.0375

Gnomad MID

AF:

0.131

Gnomad NFE

AF:

0.0418

Gnomad OTH

AF:

0.137

GnomAD2 exomes

AF:

0.0799

AC:

20030

AN:

250758

AF XY:

0.0708

show subpopulations

Gnomad AFR exome

AF:

0.453

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.0778

Gnomad EAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0621

GnomAD4 exome

AF:

0.0538

AC:

78638

AN:

1461696

Hom.:

5455

Cov.:

AF XY:

0.0526

AC XY:

38270

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.464

AC:

15531

AN:

33458

American (AMR)

AF:

0.112

AC:

5008

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

2034

AN:

26128

East Asian (EAS)

AF:

0.0131

AC:

520

AN:

39696

South Asian (SAS)

AF:

0.0571

AC:

4921

AN:

86252

European-Finnish (FIN)

AF:

0.0355

AC:

1895

AN:

53418

Middle Eastern (MID)

AF:

0.116

AC:

667

AN:

5764

European-Non Finnish (NFE)

AF:

0.0392

AC:

43574

AN:

1111874

Other (OTH)

AF:

0.0743

AC:

4488

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3780

7560

11340

15120

18900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1862

3724

5586

7448

9310

<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:

0.162

AC:

24606

AN:

152042

Hom.:

4507

Cov.:

AF XY:

0.159

AC XY:

11824

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.452

AC:

18714

AN:

41432

American (AMR)

AF:

0.106

AC:

1626

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

288

AN:

3470

East Asian (EAS)

AF:

0.0196

AC:

101

AN:

5150

South Asian (SAS)

AF:

0.0616

AC:

297

AN:

4818

European-Finnish (FIN)

AF:

0.0375

AC:

398

AN:

10600

Middle Eastern (MID)

AF:

0.127

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0418

AC:

2845

AN:

67984

Other (OTH)

AF:

0.135

AC:

286

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

793

1586

2378

3171

3964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<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:

0.0792

Hom.:

5825

Bravo

AF:

0.179

TwinsUK

AF:

0.0415

AC:

154

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.443

AC:

1951

ESP6500EA

AF:

0.0438

AC:

377

ExAC

AF:

0.0847

AC:

10287

Asia WGS

AF:

0.0910

AC:

316

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Amelogenesis imperfecta (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.1

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.053

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.13

MetaRNN

Benign

0.000061

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.7

PhyloP100

-0.71

PrimateAI

Benign

0.38

PROVEAN

Benign

3.7

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

0.88

Polyphen

0.0

Vest4

0.015

MPC

0.024

ClinPred

0.0062

GERP RS

0.53

Varity_R

0.035

gMVP

0.089

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over