4-70632586-G-A

Position:

• chr4-70632586-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.467

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
ENAM	NM_031889.3	c.169-65G>A		intron_variant		ENST00000396073.4	NP_114095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENAM	ENST00000396073.4	c.169-65G>A		intron_variant		1	NM_031889.3	ENSP00000379383	P1

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14192 AN: 151958 Hom.: 1198 Cov.: 32

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

Gnomad4 AFR exome AF: 0.237

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.0592

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0393

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.0934 AC: 14208 AN: 152076 Hom.: 1202 Cov.: 32 AF XY: 0.0921 AC XY: 6851 AN XY: 74354

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.0511

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0659

Gnomad4 FIN AF: 0.0367

Gnomad4 NFE AF: 0.0411

Gnomad4 OTH AF: 0.0865

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs144929717; hg19: chr4-71498303;