rs7671281

Positions:

chr4-70643369-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENAM	NM_031889.3 linkuse as main transcript	c.1943T>C	p.Ile648Thr	missense_variant	9/9	ENST00000396073.4	NP_114095.2
ENAM	NM_001368133.1 linkuse as main transcript	c.1289T>C	p.Ile430Thr	missense_variant	2/2		NP_001355062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4 linkuse as main transcript	c.1943T>C	p.Ile648Thr	missense_variant	9/9	1	NM_031889.3	ENSP00000379383	P1
	ENST00000472903.5 linkuse as main transcript	n.99+5526T>C		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes

AF:

0.0799

AC:

20030

AN:

250758

Hom.:

2130

AF XY:

0.0708

AC XY:

9601

AN XY:

135522

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 SAS exome

AF:

0.0571

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

Gnomad4 AFR exome

AF:

0.464

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.0778

Gnomad4 EAS exome

AF:

0.0131

Gnomad4 SAS exome

AF:

0.0571

Gnomad4 FIN exome

AF:

0.0355

Gnomad4 NFE exome

AF:

0.0392

Gnomad4 OTH exome

AF:

0.0743

GnomAD4 genome

AF:

0.162

AC:

24606

AN:

152042

Hom.:

4507

Cov.:

AF XY:

0.159

AC XY:

11824

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.452

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.0830

Gnomad4 EAS

AF:

0.0196

Gnomad4 SAS

AF:

0.0616

Gnomad4 FIN

AF:

0.0375

Gnomad4 NFE

AF:

0.0418

Gnomad4 OTH

AF:

0.135

Alfa

AF:

0.0660

Hom.:

2091

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Amelogenesis imperfecta

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign

0.043

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.1

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

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over