rs35266919

chr4-70603268-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_016519.6(AMBN):c.657A>G(p.Gln219=) 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 (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2394 hom., cov: 32)
  • Exomes 𝑓: 0.20 (33602 hom.)
• Consequence: AMBN NM_016519.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Benign. Variant got -15 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 id is 3059460.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
AMBN	NM_016519.6	c.657A>G	p.Gln219=	synonymous_variant	10/13	ENST00000322937.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMBN	ENST00000322937.10	c.657A>G	p.Gln219=	synonymous_variant	10/13	1	NM_016519.6	P1
AMBN	ENST00000449493.2	c.612A>G	p.Gln204=	synonymous_variant	10/13	5

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

GnomAD3 exomes AF: 0.153 AC: 38192 AN: 250438 Hom.: 3782 AF XY: 0.154 AC XY: 20813 AN XY: 135460

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 SAS exome AF: 0.0689

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

Gnomad4 AFR exome AF: 0.0550

Gnomad4 AMR exome AF: 0.0843

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.0704

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.176

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

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.00597

Gnomad4 SAS AF: 0.0702

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.232

Gnomad4 OTH AF: 0.128

Alfa AF: 0.196 Hom.: 2261

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: criteria provided, single submitter

Submissions by phenotype

AMBN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

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: rs35266919; hg19: chr4-71468985; COSMIC: COSV59828311;