4-70603887-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.878

Publications

18 publications found

Variant links:

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

AMBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016519.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	NM_016519.6	MANE Select	c.764C>T	p.Ala255Val	missense	Exon 12 of 13	NP_057603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMBN	ENST00000322937.10	TSL:1 MANE Select	c.764C>T	p.Ala255Val	missense	Exon 12 of 13	ENSP00000313809.6
	AMBN	ENST00000449493.2	TSL:5	c.719C>T	p.Ala240Val	missense	Exon 12 of 13	ENSP00000391234.2

Frequencies

GnomAD3 genomes

AF:

0.0944

AC:

14358

AN:

152028

Hom.:

786

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0717

AC XY:

52109

AN XY:

726994

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

4622

9244

13865

18487

23109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2620

5240

7860

10480

13100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0944

AC:

14369

AN:

152146

Hom.:

785

Cov.:

AF XY:

0.0952

AC XY:

7085

AN XY:

74388

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0637

AC:

4329

AN:

67992

Other (OTH)

AF:

0.100

AC:

211

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

672

1345

2017

2690

3362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

PhyloP100

-0.88

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.10

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.021

Polyphen

0.89

Vest4

0.25

MPC

0.32

ClinPred

0.045

GERP RS

-0.77

Varity_R

0.26

gMVP

0.098

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over