4-70645119-C-G

Variant names:

• chr4-70645119-C-G
• rs7664896
• NM_031889.3:c.*264C>G

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.*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:3
• Conservation: PhyloP100: 0.622
• Publications: 8 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:58806):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ENAM	NM_031889.3	c.*264C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000396073.4	NP_114095.2
ENAM	NM_001368133.1	c.*264C>G		3_prime_UTR_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.*264C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_031889.3	ENSP00000379383.4
ENSG00000286848	ENST00000472903.5	n.99+7276C>G		intron_variant	Intron 1 of 3	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

African (AFR) AF: 0.584 AC: 6977 AN: 11938

American (AMR) AF: 0.127 AC: 2201 AN: 17366

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 1211 AN: 12942

East Asian (EAS) AF: 0.0119 AC: 363 AN: 30632

South Asian (SAS) AF: 0.0557 AC: 1749 AN: 31396

European-Finnish (FIN) AF: 0.0348 AC: 973 AN: 27970

Middle Eastern (MID) AF: 0.116 AC: 212 AN: 1830

European-Non Finnish (NFE) AF: 0.0430 AC: 10509 AN: 244114

Other (OTH) AF: 0.0977 AC: 2372 AN: 24272

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

African (AFR) AF: 0.587 AC: 24329 AN: 41418

American (AMR) AF: 0.138 AC: 2104 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0986 AC: 342 AN: 3468

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5172

South Asian (SAS) AF: 0.0624 AC: 301 AN: 4820

European-Finnish (FIN) AF: 0.0380 AC: 403 AN: 10596

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3011 AN: 68006

Other (OTH) AF: 0.174 AC: 368 AN: 2112

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:3

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

- -

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	-0.87
CADD	Benign	4.7
DANN	Benign	0.55
PhyloP100		0.62
Mutation Taster		=100/0	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: rs7664896; hg19: chr4-71510836;