4-70645542-G-C

Variant names:

• chr4-70645542-G-C
• rs7665492
• NM_031889.3:c.*687G>C

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.*687G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,274 control chromosomes in the GnomAD database, including 8,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (8850 hom., cov: 31)
  • Exomes 𝑓: 0.075 (1 hom.)
• Consequence: ENAM NM_031889.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 7 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: SD, AD 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=-0.91).
• BP6: Variant 4-70645542-G-C is Benign according to our data. Variant chr4-70645542-G-C is described in ClinVar as Benign. ClinVar VariationId is 349520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031889.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAM	NM_031889.3	MANE Select	c.*687G>C		3_prime_UTR	Exon 9 of 9	NP_114095.2	Q9NRM1
	ENAM	NM_001368133.1		c.*687G>C		3_prime_UTR	Exon 2 of 2	NP_001355062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENAM	ENST00000396073.4	TSL:1 MANE Select	c.*687G>C		3_prime_UTR	Exon 9 of 9	ENSP00000379383.4	Q9NRM1
	ENSG00000286848	ENST00000472903.5	TSL:5	n.99+7699G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33158 AN: 151050 Hom.: 8808 Cov.: 31

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0987

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.0755 AC: 8 AN: 106 Hom.: 1 Cov.: 0 AF XY: 0.0606 AC XY: 4 AN XY: 66

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.167 AC: 2 AN: 12

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

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

South Asian (SAS) AC: 0 AN: 0

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0682 AC: 6 AN: 88

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.220 AC: 33257 AN: 151168 Hom.: 8850 Cov.: 31 AF XY: 0.217 AC XY: 15983 AN XY: 73776

African (AFR) AF: 0.641 AC: 26440 AN: 41280

American (AMR) AF: 0.144 AC: 2185 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 342 AN: 3466

East Asian (EAS) AF: 0.0196 AC: 101 AN: 5144

South Asian (SAS) AF: 0.0643 AC: 306 AN: 4758

European-Finnish (FIN) AF: 0.0389 AC: 402 AN: 10328

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.0447 AC: 3030 AN: 67742

Other (OTH) AF: 0.185 AC: 389 AN: 2100

Alfa AF: 0.147 Hom.: 660

Bravo AF: 0.245

Asia WGS AF: 0.105 AC: 363 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amelogenesis imperfecta (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.88
DANN	Benign	0.53
PhyloP100		-1.3
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: rs7665492; hg19: chr4-71511259;