rs3796704

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.2288G>A(p.Arg763Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,613,886 control chromosomes in the GnomAD database, including 5,902 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 0.12 ( 2366 hom., cov: 32)

Exomes 𝑓: 0.050 ( 3536 hom. )

Consequence

ENAM
NM_031889.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.52

Publications

48 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=0.0038062036).

BP6

Variant 4-70643714-G-A is Benign according to our data. Variant chr4-70643714-G-A is described in ClinVar as Benign. ClinVar VariationId is 261985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 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.2288G>A	p.Arg763Gln	missense	Exon 9 of 9	NP_114095.2	Q9NRM1
	ENAM	NM_001368133.1		c.1634G>A	p.Arg545Gln	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.2288G>A	p.Arg763Gln	missense	Exon 9 of 9	ENSP00000379383.4	Q9NRM1
	ENSG00000286848	ENST00000472903.5	TSL:5	n.99+5871G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18860

AN:

151966

Hom.:

2353

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0940

Gnomad ASJ

AF:

0.0700

Gnomad EAS

AF:

0.0194

Gnomad SAS

AF:

0.0603

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.0698

AC:

17513

AN:

250996

AF XY:

0.0637

show subpopulations

Gnomad AFR exome

AF:

0.325

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0667

Gnomad EAS exome

AF:

0.0160

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0414

Gnomad OTH exome

AF:

0.0572

GnomAD4 exome

AF:

0.0500

AC:

73136

AN:

1461802

Hom.:

3536

Cov.:

AF XY:

0.0493

AC XY:

35828

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.333

AC:

11139

AN:

33472

American (AMR)

AF:

0.105

AC:

4680

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

1778

AN:

26136

East Asian (EAS)

AF:

0.0131

AC:

520

AN:

39696

South Asian (SAS)

AF:

0.0564

AC:

4866

AN:

86258

European-Finnish (FIN)

AF:

0.0357

AC:

1905

AN:

53416

Middle Eastern (MID)

AF:

0.106

AC:

610

AN:

5766

European-Non Finnish (NFE)

AF:

0.0393

AC:

43755

AN:

1111948

Other (OTH)

AF:

0.0643

AC:

3883

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3931

7862

11792

15723

19654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1826

3652

5478

7304

9130

<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:

0.124

AC:

18906

AN:

152084

Hom.:

2366

Cov.:

AF XY:

0.123

AC XY:

9179

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.322

AC:

13342

AN:

41412

American (AMR)

AF:

0.0940

AC:

1437

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0700

AC:

243

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5182

South Asian (SAS)

AF:

0.0606

AC:

292

AN:

4822

European-Finnish (FIN)

AF:

0.0377

AC:

399

AN:

10594

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0414

AC:

2818

AN:

67996

Other (OTH)

AF:

0.108

AC:

228

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

699

1398

2097

2796

3495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.0678

Hom.:

3808

Bravo

AF:

0.137

TwinsUK

AF:

0.0413

AC:

153

ALSPAC

AF:

0.0361

AC:

139

ESP6500AA

AF:

0.322

AC:

1419

ESP6500EA

AF:

0.0433

AC:

372

ExAC

AF:

0.0723

AC:

8773

Asia WGS

AF:

0.0730

AC:

254

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

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.091

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0038

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

PhyloP100

3.5

PrimateAI

Benign

0.39

PROVEAN

Benign

0.77

REVEL

Benign

0.025

Sift

Uncertain

0.024

Sift4G

Benign

0.16

Polyphen

0.0020

Vest4

0.080

MPC

0.023

ClinPred

0.013

GERP RS

3.3

Varity_R

0.033

gMVP

0.083

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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