NM_016519.6:c.764C>T

Variant names:

• chr4-70603887-C-T
• rs7439186
• NM_016519.6:c.764C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_016519.6(AMBN):​c.764C>T​(p.Ala255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,613,484 control chromosomes in the GnomAD database, including 4,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.094 (785 hom., cov: 32)
  • Exomes 𝑓: 0.070 (4054 hom.)
• Consequence: AMBN NM_016519.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.878
• Publications: 18 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027917027).
• BP6: Variant 4-70603887-C-T is Benign according to our data. Variant chr4-70603887-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056421.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6	c.764C>T	p.Ala255Val	missense_variant	Exon 12 of 13	ENST00000322937.10	NP_057603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10	c.764C>T	p.Ala255Val	missense_variant	Exon 12 of 13	1	NM_016519.6	ENSP00000313809.6
AMBN	ENST00000449493.2	c.719C>T	p.Ala240Val	missense_variant	Exon 12 of 13	5		ENSP00000391234.2

Frequencies

GnomAD3 genomes AF: 0.0944 AC: 14358 AN: 152028 Hom.: 786 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0874

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0710

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0855 AC: 21442 AN: 250910 AF XY: 0.0852

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0751

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.124

Gnomad FIN exome AF: 0.0676

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0884

GnomAD4 exome AF: 0.0703 AC: 102713 AN: 1461338 Hom.: 4054 Cov.: 31 AF XY: 0.0717 AC XY: 52109 AN XY: 726994

African (AFR) AF: 0.145 AC: 4869 AN: 33470

American (AMR) AF: 0.0758 AC: 3389 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3783 AN: 26112

East Asian (EAS) AF: 0.128 AC: 5084 AN: 39636

South Asian (SAS) AF: 0.113 AC: 9732 AN: 86216

European-Finnish (FIN) AF: 0.0651 AC: 3478 AN: 53394

Middle Eastern (MID) AF: 0.138 AC: 798 AN: 5766

European-Non Finnish (NFE) AF: 0.0598 AC: 66500 AN: 1111664

Other (OTH) AF: 0.0842 AC: 5080 AN: 60366

GnomAD4 genome AF: 0.0944 AC: 14369 AN: 152146 Hom.: 785 Cov.: 32 AF XY: 0.0952 AC XY: 7085 AN XY: 74388

African (AFR) AF: 0.140 AC: 5816 AN: 41482

American (AMR) AF: 0.0871 AC: 1333 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3468

East Asian (EAS) AF: 0.137 AC: 707 AN: 5172

South Asian (SAS) AF: 0.117 AC: 566 AN: 4822

European-Finnish (FIN) AF: 0.0710 AC: 752 AN: 10598

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0637 AC: 4329 AN: 67992

Other (OTH) AF: 0.100 AC: 211 AN: 2110

Alfa AF: 0.0770 Hom.: 2035

Bravo AF: 0.0968

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.133 AC: 587

ESP6500EA AF: 0.0721 AC: 620

ExAC AF: 0.0868 AC: 10543

Asia WGS AF: 0.136 AC: 474 AN: 3478

EpiCase AF: 0.0694

EpiControl AF: 0.0669

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AMBN-related disorder Benign:1

Mar 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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		-0.88
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	D;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.89	P;.;.
Vest4		0.25
MPC		0.32
ClinPred		0.045	T
GERP RS		-0.77
Varity_R		0.26
gMVP		0.098
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7439186; hg19: chr4-71469604; COSMIC: COSV59825990;