rs3796704

chr4-70643714-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.52

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]

(HGNC:):

ACMG classification

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	c.2288G>A	p.Arg763Gln	missense_variant	9/9	ENST00000396073.4
ENAM	NM_001368133.1	c.1634G>A	p.Arg545Gln	missense_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18860 AN: 151966 Hom.: 2353 Cov.: 32

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

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.: 34 AF XY: 0.0493 AC XY: 35828 AN XY: 727206

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.: 32 AF XY: 0.123 AC XY: 9179 AN XY: 74356

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

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	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.025
Sift	Uncertain	0.024	D
Sift4G	Benign	0.16	T
Polyphen		0.0020	B
Vest4		0.080
MPC		0.023
ClinPred		0.013	T
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

Other links and lift over

dbSNP: rs3796704; hg19: chr4-71509431; COSMIC: COSV68535409; COSMIC: COSV68535409;