chr4-70643369-T-C

Variant names:

• chr4-70643369-T-C
• rs7671281
• NM_031889.3:c.1943T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:4
• Conservation: PhyloP100: -0.714
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 1B

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 1C

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• amelogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286848 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ENAM	NM_031889.3	c.1943T>C	p.Ile648Thr	missense_variant	Exon 9 of 9	ENST00000396073.4	NP_114095.2
ENAM	NM_001368133.1	c.1289T>C	p.Ile430Thr	missense_variant	Exon 2 of 2		NP_001355062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4	c.1943T>C	p.Ile648Thr	missense_variant	Exon 9 of 9	1	NM_031889.3	ENSP00000379383.4
ENSG00000286848	ENST00000472903.5	n.99+5526T>C		intron_variant	Intron 1 of 3	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

GnomAD2 exomes AF: 0.0799 AC: 20030 AN: 250758 AF XY: 0.0708

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 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

African (AFR) AF: 0.464 AC: 15531 AN: 33458

American (AMR) AF: 0.112 AC: 5008 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 2034 AN: 26128

East Asian (EAS) AF: 0.0131 AC: 520 AN: 39696

South Asian (SAS) AF: 0.0571 AC: 4921 AN: 86252

European-Finnish (FIN) AF: 0.0355 AC: 1895 AN: 53418

Middle Eastern (MID) AF: 0.116 AC: 667 AN: 5764

European-Non Finnish (NFE) AF: 0.0392 AC: 43574 AN: 1111874

Other (OTH) AF: 0.0743 AC: 4488 AN: 60390

GnomAD4 genome AF: 0.162 AC: 24606 AN: 152042 Hom.: 4507 Cov.: 31 AF XY: 0.159 AC XY: 11824 AN XY: 74336

African (AFR) AF: 0.452 AC: 18714 AN: 41432

American (AMR) AF: 0.106 AC: 1626 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 288 AN: 3470

East Asian (EAS) AF: 0.0196 AC: 101 AN: 5150

South Asian (SAS) AF: 0.0616 AC: 297 AN: 4818

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10600

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0418 AC: 2845 AN: 67984

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.0792 Hom.: 5825

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

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Amelogenesis imperfecta Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.71
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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