rs36094464

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014208.3(DSPP):c.202A>T(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,918 control chromosomes in the GnomAD database, including 7,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2520 hom., cov: 32)

Exomes 𝑓: 0.068 ( 5084 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: -0.106

Publications

22 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, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
dentinogenesis imperfecta
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dentinogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
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:

DMP1-AS1 (HGNC:58144):

DMP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010052949).

BP6

Variant 4-87612388-A-T is Benign according to our data. Variant chr4-87612388-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 16858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	NM_014208.3	MANE Select	c.202A>T	p.Arg68Trp	missense	Exon 4 of 5	NP_055023.2	Q9NZW4
	DMP1-AS1	NR_198971.1		n.367-43855T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSPP	ENST00000651931.1	MANE Select	c.202A>T	p.Arg68Trp	missense	Exon 4 of 5	ENSP00000498766.1	Q9NZW4
DMP1-AS1	ENST00000506480.5	TSL:3	n.323-43855T>A		intron	N/A
DMP1-AS1	ENST00000829286.1		n.357-43855T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21091

AN:

152042

Hom.:

2517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.319

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0638

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0646

Gnomad OTH

AF:

0.110

GnomAD2 exomes

AF:

0.0848

AC:

21119

AN:

249020

AF XY:

0.0826

show subpopulations

Gnomad AFR exome

AF:

0.325

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.0910

Gnomad EAS exome

AF:

0.0128

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0768

GnomAD4 exome

AF:

0.0685

AC:

100116

AN:

1461758

Hom.:

5084

Cov.:

AF XY:

0.0685

AC XY:

49814

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.328

AC:

10995

AN:

33472

American (AMR)

AF:

0.0467

AC:

2087

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0906

AC:

2369

AN:

26136

East Asian (EAS)

AF:

0.0105

AC:

415

AN:

39696

South Asian (SAS)

AF:

0.0720

AC:

6205

AN:

86240

European-Finnish (FIN)

AF:

0.145

AC:

7725

AN:

53418

Middle Eastern (MID)

AF:

0.113

AC:

651

AN:

5768

European-Non Finnish (NFE)

AF:

0.0583

AC:

64803

AN:

1111930

Other (OTH)

AF:

0.0806

AC:

4866

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5907

11815

17722

23630

29537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2436

4872

7308

9744

12180

<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:

0.139

AC:

21120

AN:

152160

Hom.:

2520

Cov.:

AF XY:

0.139

AC XY:

10374

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.319

AC:

13207

AN:

41460

American (AMR)

AF:

0.0636

AC:

973

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0862

AC:

299

AN:

3470

East Asian (EAS)

AF:

0.0114

AC:

AN:

5174

South Asian (SAS)

AF:

0.0740

AC:

357

AN:

4826

European-Finnish (FIN)

AF:

0.146

AC:

1545

AN:

10602

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0646

AC:

4396

AN:

68016

Other (OTH)

AF:

0.109

AC:

230

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

819

1639

2458

3278

4097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.0755

Hom.:

451

Bravo

AF:

0.139

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0501

AC:

193

ESP6500AA

AF:

0.309

AC:

1194

ESP6500EA

AF:

0.0647

AC:

537

ExAC

AF:

0.0903

AC:

10915

Asia WGS

AF:

0.0510

AC:

179

AN:

3478

EpiCase

AF:

0.0638

EpiControl

AF:

0.0654

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Dentinogenesis imperfecta type 2 (2)

Dentinogenesis imperfecta (1)

DSPP-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.59

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

-0.11

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift4G

Uncertain

0.0040

Polyphen

0.14

Vest4

0.22

ClinPred

0.0056

GERP RS

-2.3

Varity_R

0.27

gMVP

0.19

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over