rs7671281

chr4-70643369-T-C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.714

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=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	UniProt
ENAM	NM_031889.3	c.1943T>C	p.Ile648Thr	missense_variant	9/9	ENST00000396073.4
ENAM	NM_001368133.1	c.1289T>C	p.Ile430Thr	missense_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24529 AN: 151924 Hom.: 4479 Cov.: 31

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

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.: 34 AF XY: 0.0526 AC XY: 38270 AN XY: 727144

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.: 31 AF XY: 0.159 AC XY: 11824 AN XY: 74336

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: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 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	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.1
Dann	Benign	0.28
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.000061	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.7	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	3.7	N
REVEL	Benign	0.055
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.024
ClinPred		0.0062	T
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

Other links and lift over

dbSNP: rs7671281; hg19: chr4-71509086; COSMIC: COSV68535406; COSMIC: COSV68535406;