chr4-70643714-G-A

Position:

chr4-70643714-G-A

Variant summary

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

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=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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENAM	NM_031889.3 linkuse as main transcript	c.2288G>A	p.Arg763Gln	missense_variant	9/9	ENST00000396073.4
ENAM	NM_001368133.1 linkuse as main transcript	c.1634G>A	p.Arg545Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENAM	ENST00000396073.4 linkuse as main transcript	c.2288G>A	p.Arg763Gln	missense_variant	9/9	1	NM_031889.3	P1
	ENST00000472903.5 linkuse as main transcript	n.99+5871G>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes

AF:

0.0698

AC:

17513

AN:

250996

Hom.:

1278

AF XY:

0.0637

AC XY:

8648

AN XY:

135758

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 SAS exome

AF:

0.0561

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

Gnomad4 AFR exome

AF:

0.333

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.0680

Gnomad4 EAS exome

AF:

0.0131

Gnomad4 SAS exome

AF:

0.0564

Gnomad4 FIN exome

AF:

0.0357

Gnomad4 NFE exome

AF:

0.0393

Gnomad4 OTH exome

AF:

0.0643

GnomAD4 genome

AF:

0.124

AC:

18906

AN:

152084

Hom.:

2366

Cov.:

AF XY:

0.123

AC XY:

9179

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.0940

Gnomad4 ASJ

AF:

0.0700

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.0606

Gnomad4 FIN

AF:

0.0377

Gnomad4 NFE

AF:

0.0414

Gnomad4 OTH

AF:

0.108

Alfa

AF:

0.0581

Hom.:

1276

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

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

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 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

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

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

MutationTaster

Benign

1.0

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

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

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