rs12640848

Variant names:

• chr4-70640695-A-G
• rs12640848
• NM_031889.3:c.589-1320A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031889.3(ENAM):​c.589-1320A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 151,924 control chromosomes in the GnomAD database, including 21,875 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (21875 hom., cov: 31)
• Consequence: ENAM NM_031889.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.300
• Publications: 38 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENAM	NM_031889.3	c.589-1320A>G		intron_variant	Intron 8 of 8	ENST00000396073.4	NP_114095.2
ENAM	NM_001368133.1	c.-66-1320A>G		intron_variant	Intron 1 of 1		NP_001355062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4	c.589-1320A>G		intron_variant	Intron 8 of 8	1	NM_031889.3	ENSP00000379383.4
ENAM	ENST00000472597.1	c.-66-1320A>G		intron_variant	Intron 1 of 1	4		ENSP00000497682.1
ENSG00000286848	ENST00000472903.5	n.99+2852A>G		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72126 AN: 151806 Hom.: 21885 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.475 AC: 72102 AN: 151924 Hom.: 21875 Cov.: 31 AF XY: 0.466 AC XY: 34573 AN XY: 74200

African (AFR) AF: 0.124 AC: 5132 AN: 41488

American (AMR) AF: 0.402 AC: 6125 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3470

East Asian (EAS) AF: 0.229 AC: 1183 AN: 5162

South Asian (SAS) AF: 0.484 AC: 2326 AN: 4806

European-Finnish (FIN) AF: 0.622 AC: 6534 AN: 10504

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46889 AN: 67942

Other (OTH) AF: 0.491 AC: 1035 AN: 2108

Alfa AF: 0.625 Hom.: 51018

Bravo AF: 0.438

Asia WGS AF: 0.310 AC: 1080 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.32
PhyloP100		0.30
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: rs12640848; hg19: chr4-71506412;