rs61731011

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014208.3(DSPP):c.1060C>T(p.Arg354Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,718 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R354H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 36 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 1.97

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036010146).

BP6

Variant 4-87613246-C-T is Benign according to our data. Variant chr4-87613246-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260354.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00369 (562/152178) while in subpopulation SAS AF = 0.00998 (48/4808). AF 95% confidence interval is 0.00774. There are 3 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 562 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.1060C>T	p.Arg354Cys	missense_variant	Exon 4 of 5	ENST00000651931.1	NP_055023.2	Q9NZW4
DMP1-AS1	NR_198971.1 link	n.367-44713G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.1060C>T	p.Arg354Cys	missense_variant	Exon 4 of 5		NM_014208.3	ENSP00000498766.1		Q9NZW4

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00977

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00438

AC:

1080

AN:

246612

AF XY:

0.00461

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00363

Gnomad ASJ exome

AF:

0.00180

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00433

GnomAD4 exome

AF:

0.00510

AC:

7451

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3805

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00340

AC:

152

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

26136

East Asian (EAS)

AF:

0.000882

AC:

AN:

39698

South Asian (SAS)

AF:

0.00864

AC:

745

AN:

86252

European-Finnish (FIN)

AF:

0.00320

AC:

170

AN:

53104

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00538

AC:

5986

AN:

1111990

Other (OTH)

AF:

0.00437

AC:

264

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

435

870

1305

1740

2175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

234

468

702

936

1170

<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:

0.00369

AC:

562

AN:

152178

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000843

AC:

AN:

41514

American (AMR)

AF:

0.00511

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00998

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00500

AC:

340

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00445

Hom.:

Bravo

AF:

0.00332

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000794

AC:

ESP6500EA

AF:

0.00464

AC:

ExAC

AF:

0.00441

AC:

532

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

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

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DSPP: BP4, BS2 -

Apr 14, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 25, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1060C>T (p.R354C) alteration is located in exon 4 (coding exon 3) of the DSPP gene. This alteration results from a C to T substitution at nucleotide position 1060, causing the arginine (R) at amino acid position 354 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

Uncertain:1

May 14, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.077

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.0

PhyloP100

2.0

PROVEAN

Benign

-0.40

REVEL

Benign

0.27

Sift4G

Uncertain

0.041

Polyphen

0.85

Vest4

0.12

MVP

0.70

ClinPred

0.011

GERP RS

1.3

Varity_R

0.13

gMVP

0.0076

Mutation Taster

=100/0

polymorphism

(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