NM_014208.3:c.3681C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_014208.3(DSPP):c.3681C>A(p.Asp1227Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 127,194 control chromosomes in the GnomAD database, including 202 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1227D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.045 ( 202 hom., cov: 32)

Exomes 𝑓: 0.011 ( 1115 hom. )

Failed GnomAD Quality Control

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.44

Publications

1 publications found

Variant links:

Genes affected

DSPP (HGNC:3054): (dentin sialophosphoprotein) This gene encodes a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of proteins. The encoded preproprotein is secreted by odontoblasts and proteolytically processed to generate two principal proteins of the dentin extracellular matrix of the tooth, dentin sialoprotein and dentin phosphoprotein. These two protein products may play distinct but related roles in dentin mineralization. Mutations in this gene are associated with dentinogenesis imperfecta and dentin dysplasia. This gene is present in a gene cluster on chromosome 4. Allelic differences due to repeat polymorphisms have been found for this gene. [provided by RefSeq, Jan 2016]

DSPP Gene-Disease associations (from GenCC):

deafness, autosomal dominant 39, with dentinogenesis imperfecta 1
Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
dentinogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dentinogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
dentinogenesis imperfecta type 3
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
dentin dysplasia type I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dentin dysplasia type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DSPP links:

ENSG00000249001 (HGNC:58144):

ENSG00000249001 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036220253).

BP6

Variant 4-87616343-C-A is Benign according to our data. Variant chr4-87616343-C-A is described in ClinVar as Benign. ClinVar VariationId is 523082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.3681C>A	p.Asp1227Glu	missense_variant	Exon 5 of 5	ENST00000651931.1	NP_055023.2	Q9NZW4
DMP1-AS1	NR_198971.1 link	n.367-47810G>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.3681C>A	p.Asp1227Glu	missense_variant	Exon 5 of 5		NM_014208.3	ENSP00000498766.1		Q9NZW4

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

5685

AN:

127092

Hom.:

201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.0322

Gnomad EAS

AF:

0.00410

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.0366

Gnomad MID

AF:

0.0430

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.0324

GnomAD2 exomes

AF:

0.00545

AC:

796

AN:

146032

AF XY:

0.00481

show subpopulations

Gnomad AFR exome

AF:

0.0949

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.000965

Gnomad EAS exome

AF:

0.000281

Gnomad FIN exome

AF:

0.00598

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00288

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0115

AC:

14402

AN:

1256910

Hom.:

1115

Cov.:

203

AF XY:

0.0120

AC XY:

7413

AN XY:

619838

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.118

AC:

2203

AN:

18636

American (AMR)

AF:

0.0120

AC:

378

AN:

31622

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

540

AN:

22112

East Asian (EAS)

AF:

0.00379

AC:

127

AN:

33546

South Asian (SAS)

AF:

0.0113

AC:

795

AN:

70192

European-Finnish (FIN)

AF:

0.0459

AC:

1985

AN:

43254

Middle Eastern (MID)

AF:

0.0232

AC:

116

AN:

5010

European-Non Finnish (NFE)

AF:

0.00737

AC:

7231

AN:

981380

Other (OTH)

AF:

0.0201

AC:

1027

AN:

51158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.271

Heterozygous variant carriers

1434

2867

4301

5734

7168

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.0448

AC:

5703

AN:

127194

Hom.:

202

Cov.:

AF XY:

0.0439

AC XY:

2735

AN XY:

62260

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.128

AC:

3525

AN:

27488

American (AMR)

AF:

0.0229

AC:

312

AN:

13654

Ashkenazi Jewish (ASJ)

AF:

0.0322

AC:

104

AN:

3228

East Asian (EAS)

AF:

0.00411

AC:

AN:

4870

South Asian (SAS)

AF:

0.0153

AC:

AN:

4238

European-Finnish (FIN)

AF:

0.0366

AC:

334

AN:

9132

Middle Eastern (MID)

AF:

0.0504

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0206

AC:

1273

AN:

61676

Other (OTH)

AF:

0.0320

AC:

AN:

1812

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.306

Heterozygous variant carriers

392

784

1176

1568

1960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0000315

Hom.:

ExAC

AF:

0.0000427

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.042

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.062

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.25

M_CAP

Benign

0.038

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.0

PhyloP100

-2.4

PROVEAN

Benign

0.50

REVEL

Benign

0.25

Sift4G

Benign

0.34

Polyphen

0.99

Vest4

0.091

MutPred

0.27

Gain of glycosylation at S1226 (P = 2e-04);

MVP

0.44

ClinPred

0.017

GERP RS

-1.5

Varity_R

0.057

gMVP

0.00026

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over