Genetic Variant ENAM:c.169-65G>A (chr4-70632586-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_031889.3(ENAM):c.169-65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,163,246 control chromosomes in the GnomAD database, including 2,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 1202 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1704 hom. )

Consequence

ENAM
NM_031889.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.467

Publications

6 publications found

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 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

ENAM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 4-70632586-G-A is Benign according to our data. Variant chr4-70632586-G-A is described in ClinVar as [Benign]. Clinvar id is 1265615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAM	NM_031889.3 link	c.169-65G>A		intron_variant	Intron 4 of 8	ENST00000396073.4	NP_114095.2	Q9NRM1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4 link	c.169-65G>A		intron_variant	Intron 4 of 8	1	NM_031889.3	ENSP00000379383.4		Q9NRM1

Frequencies

GnomAD3 genomes

AF:

0.0934

AC:

14192

AN:

151958

Hom.:

1198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0513

Gnomad ASJ

AF:

0.0674

Gnomad EAS

AF:

0.0191

Gnomad SAS

AF:

0.0656

Gnomad FIN

AF:

0.0367

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.0883

GnomAD4 exome

AF:

0.0457

AC:

46247

AN:

1011170

Hom.:

1704

AF XY:

0.0457

AC XY:

23901

AN XY:

523062

show subpopulations

African (AFR)

AF:

0.237

AC:

5833

AN:

24654

American (AMR)

AF:

0.0309

AC:

1363

AN:

44104

Ashkenazi Jewish (ASJ)

AF:

0.0648

AC:

1511

AN:

23306

East Asian (EAS)

AF:

0.0124

AC:

463

AN:

37418

South Asian (SAS)

AF:

0.0592

AC:

4558

AN:

76938

European-Finnish (FIN)

AF:

0.0353

AC:

1877

AN:

53182

Middle Eastern (MID)

AF:

0.104

AC:

506

AN:

4850

European-Non Finnish (NFE)

AF:

0.0393

AC:

27523

AN:

701154

Other (OTH)

AF:

0.0573

AC:

2613

AN:

45564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

2039

4078

6117

8156

10195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0934

AC:

14208

AN:

152076

Hom.:

1202

Cov.:

AF XY:

0.0921

AC XY:

6851

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.226

AC:

9373

AN:

41484

American (AMR)

AF:

0.0511

AC:

781

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0674

AC:

234

AN:

3470

East Asian (EAS)

AF:

0.0189

AC:

AN:

5184

South Asian (SAS)

AF:

0.0659

AC:

318

AN:

4826

European-Finnish (FIN)

AF:

0.0367

AC:

389

AN:

10590

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0411

AC:

2790

AN:

67926

Other (OTH)

AF:

0.0865

AC:

183

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

603

1205

1808

2410

3013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0722

Hom.:

106

Bravo

AF:

0.0998

Asia WGS

AF:

0.0720

AC:

249

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.9

(source)

DANN

Benign

0.56

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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4-70632586-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over