chr4-70628902-G-A

Variant names:

• chr4-70628902-G-A
• rs1993579
• NM_031889.3:c.-123G>A

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.-123G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,420 control chromosomes in the GnomAD database, including 9,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (9074 hom., cov: 32)
  • Exomes 𝑓: 0.040 (0 hom.)
• Consequence: ENAM NM_031889.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-70628902-G-A is Benign according to our data. Variant chr4-70628902-G-A is described in ClinVar as [Benign]. Clinvar id is 349489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAM	NM_031889.3	c.-123G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000396073.4	NP_114095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4	c.-123G>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_031889.3	ENSP00000379383.4

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33210 AN: 151882 Hom.: 9025 Cov.: 32

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.0446

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.0405 AC: 17 AN: 420 Hom.: 0 Cov.: 0 AF XY: 0.0402 AC XY: 9 AN XY: 224

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.0303 AC: 2 AN: 66

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.100 AC: 2 AN: 20

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0409 AC: 13 AN: 318

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.219 AC: 33316 AN: 152000 Hom.: 9074 Cov.: 32 AF XY: 0.214 AC XY: 15943 AN XY: 74334

African (AFR) AF: 0.649 AC: 26882 AN: 41438

American (AMR) AF: 0.116 AC: 1771 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3466

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5186

South Asian (SAS) AF: 0.0681 AC: 328 AN: 4818

European-Finnish (FIN) AF: 0.0378 AC: 400 AN: 10594

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.0446 AC: 3028 AN: 67926

Other (OTH) AF: 0.186 AC: 392 AN: 2108

Alfa AF: 0.0257 Hom.: 48

Bravo AF: 0.243

Asia WGS AF: 0.107 AC: 369 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		1.0
PromoterAI		0.0020	Neutral
Mutation Taster		=300/0	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: rs1993579; hg19: chr4-71494619;