rs35266919

Variant names:

• chr4-70603268-A-G
• rs35266919
• NM_016519.6:c.657A>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.657A>G​(p.Gln219Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,611,996 control chromosomes in the GnomAD database, including 35,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2394 hom., cov: 32)
  • Exomes 𝑓: 0.20 (33602 hom.)
• Consequence: AMBN NM_016519.6 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.03
• Publications: 12 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=-0.6).
• BP6: Variant 4-70603268-A-G is Benign according to our data. Variant chr4-70603268-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059460.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.657A>G	p.Gln219Gln	synonymous_variant	Exon 10 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.657A>G	p.Gln219Gln	synonymous_variant	Exon 10 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.612A>G	p.Gln204Gln	synonymous_variant	Exon 10 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23484 AN: 152080 Hom.: 2393 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00595

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.153 AC: 38192 AN: 250438 AF XY: 0.154

Gnomad AFR exome AF: 0.0570

Gnomad AMR exome AF: 0.0790

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.00804

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.203 AC: 296622 AN: 1459798 Hom.: 33602 Cov.: 33 AF XY: 0.199 AC XY: 144589 AN XY: 726286

African (AFR) AF: 0.0550 AC: 1841 AN: 33454

American (AMR) AF: 0.0843 AC: 3768 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3259 AN: 26114

East Asian (EAS) AF: 0.0126 AC: 499 AN: 39576

South Asian (SAS) AF: 0.0704 AC: 6069 AN: 86176

European-Finnish (FIN) AF: 0.198 AC: 10566 AN: 53344

Middle Eastern (MID) AF: 0.0485 AC: 279 AN: 5758

European-Non Finnish (NFE) AF: 0.234 AC: 259710 AN: 1110400

Other (OTH) AF: 0.176 AC: 10631 AN: 60288

GnomAD4 genome AF: 0.154 AC: 23492 AN: 152198 Hom.: 2394 Cov.: 32 AF XY: 0.149 AC XY: 11107 AN XY: 74390

African (AFR) AF: 0.0623 AC: 2587 AN: 41538

American (AMR) AF: 0.108 AC: 1657 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 410 AN: 3468

East Asian (EAS) AF: 0.00597 AC: 31 AN: 5194

South Asian (SAS) AF: 0.0702 AC: 339 AN: 4828

European-Finnish (FIN) AF: 0.192 AC: 2029 AN: 10572

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15786 AN: 67986

Other (OTH) AF: 0.128 AC: 270 AN: 2114

Alfa AF: 0.195 Hom.: 3010

Bravo AF: 0.143

Asia WGS AF: 0.0480 AC: 166 AN: 3472

EpiCase AF: 0.203

EpiControl AF: 0.201

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AMBN-related disorder Benign:1

Oct 21, 2019

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	-0.60
CADD	Benign	3.9
DANN	Benign	0.40
PhyloP100		1.0
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: rs35266919; hg19: chr4-71468985; COSMIC: COSV59828311;