rs7680880

Variant names:

• chr4-70606709-A-G
• rs7680880
• NM_016519.6:c.1323A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_016519.6(AMBN):​c.1323A>G​(p.Ala441Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,612,720 control chromosomes in the GnomAD database, including 19,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (7952 hom., cov: 32)
  • Exomes 𝑓: 0.095 (12029 hom.)
• Consequence: AMBN NM_016519.6 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.52
• Publications: 15 publications found

Genes affected

AMBN (HGNC:452): (ameloblastin) This gene encodes the nonamelogenin enamel matrix protein ameloblastin. The encoded protein may be important in enamel matrix formation and mineralization. This gene is located in the calcium-binding phosphoprotein gene cluster on chromosome 4. Mutations in this gene may be associated with dentinogenesis imperfect and autosomal dominant amylogenesis imperfect. [provided by RefSeq, Aug 2011]

AMBN Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 1F

  Inheritance: SD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 4-70606709-A-G is Benign according to our data. Variant chr4-70606709-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059474.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.1323A>G	p.Ala441Ala	synonymous_variant	Exon 13 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.1323A>G	p.Ala441Ala	synonymous_variant	Exon 13 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.1278A>G	p.Ala426Ala	synonymous_variant	Exon 13 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35291 AN: 152046 Hom.: 7922 Cov.: 32

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0917

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0757

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.129 AC: 32085 AN: 248236 AF XY: 0.123

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.0938

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0729

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0948 AC: 138464 AN: 1460556 Hom.: 12029 Cov.: 32 AF XY: 0.0950 AC XY: 69042 AN XY: 726514

African (AFR) AF: 0.609 AC: 20361 AN: 33412

American (AMR) AF: 0.102 AC: 4548 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 2339 AN: 26032

East Asian (EAS) AF: 0.151 AC: 5990 AN: 39650

South Asian (SAS) AF: 0.159 AC: 13675 AN: 86120

European-Finnish (FIN) AF: 0.102 AC: 5454 AN: 53350

Middle Eastern (MID) AF: 0.136 AC: 783 AN: 5764

European-Non Finnish (NFE) AF: 0.0700 AC: 77808 AN: 1111292

Other (OTH) AF: 0.124 AC: 7506 AN: 60336

GnomAD4 genome AF: 0.232 AC: 35377 AN: 152164 Hom.: 7952 Cov.: 32 AF XY: 0.233 AC XY: 17302 AN XY: 74392

African (AFR) AF: 0.590 AC: 24478 AN: 41468

American (AMR) AF: 0.145 AC: 2220 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0917 AC: 318 AN: 3466

East Asian (EAS) AF: 0.143 AC: 740 AN: 5178

South Asian (SAS) AF: 0.160 AC: 773 AN: 4826

European-Finnish (FIN) AF: 0.110 AC: 1167 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0757 AC: 5149 AN: 68020

Other (OTH) AF: 0.196 AC: 415 AN: 2114

Alfa AF: 0.125 Hom.: 11511

Bravo AF: 0.249

Asia WGS AF: 0.210 AC: 729 AN: 3478

EpiCase AF: 0.0755

EpiControl AF: 0.0738

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AMBN-related disorder Benign:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.075
DANN	Benign	0.34
PhyloP100		-3.5
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: rs7680880; hg19: chr4-71472426; COSMIC: COSV59825432;