rs7664896

chr4-70645119-C-G

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.*264C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 554,540 control chromosomes in the GnomAD database, including 10,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (7531 hom., cov: 32)
  • Exomes 𝑓: 0.066 (2841 hom.)
• Consequence: ENAM NM_031889.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.622

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 (BayesDel_noAF=-0.87).
• BP6: Variant 4-70645119-C-G is Benign according to our data. Variant chr4-70645119-C-G is described in ClinVar as [Benign]. Clinvar id is 349513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENAM	NM_031889.3	c.*264C>G		3_prime_UTR_variant	9/9	ENST00000396073.4
ENAM	NM_001368133.1	c.*264C>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENAM	ENST00000396073.4	c.*264C>G		3_prime_UTR_variant	9/9	1	NM_031889.3	P1
	ENST00000472903.5	n.99+7276C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30921 AN: 151962 Hom.: 7488 Cov.: 32

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0986

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.0660 AC: 26567 AN: 402460 Hom.: 2841 Cov.: 0 AF XY: 0.0631 AC XY: 13109 AN XY: 207858

Gnomad4 AFR exome AF: 0.584

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.0936

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0557

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0430

Gnomad4 OTH exome AF: 0.0977

GnomAD4 genome AF: 0.204 AC: 31022 AN: 152080 Hom.: 7531 Cov.: 32 AF XY: 0.200 AC XY: 14905 AN XY: 74346

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0986

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0624

Gnomad4 FIN AF: 0.0380

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.174

Alfa AF: 0.132 Hom.: 555

Bravo AF: 0.227

Asia WGS AF: 0.103 AC: 359 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.7
Dann	Benign	0.55

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

Other links and lift over

dbSNP: rs7664896; hg19: chr4-71510836;