Variant 4-70598364-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016519.6(AMBN):c.144A>C(p.Arg48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,583,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

AMBN
NM_016519.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMBN	NM_016519.6 link	c.144A>C	p.Arg48Ser	missense_variant	Exon 4 of 13	ENST00000322937.10	NP_057603.1	Q9NP70-1Q546D7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMBN	ENST00000322937.10 link	c.144A>C	p.Arg48Ser	missense_variant	Exon 4 of 13	1	NM_016519.6	ENSP00000313809.6		Q9NP70-1
AMBN	ENST00000449493.2 link	c.144A>C	p.Arg48Ser	missense_variant	Exon 4 of 13	5		ENSP00000391234.2		Q9NP70-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

234472

Hom.:

AF XY:

0.0000236

AC XY:

AN XY:

127276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000670

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000419

AC:

AN:

1431416

Hom.:

Cov.:

AF XY:

0.00000421

AC XY:

AN XY:

712018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000735

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.144A>C (p.R48S) alteration is located in exon 4 (coding exon 4) of the AMBN gene. This alteration results from a A to C substitution at nucleotide position 144, causing the arginine (R) at amino acid position 48 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.3

D;.;D

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;.;D

Sift4G

Benign

0.067

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.91

MutPred

0.82

Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);

MVP

0.61

MPC

0.39

ClinPred

0.99

GERP RS

3.3

Varity_R

0.74

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over