4-87615883-A-G

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.3221A>G(p.Asp1074Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 888,802 control chromosomes in the GnomAD database, including 6,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1074Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 3113 hom., cov: 24)

Exomes 𝑓: 0.044 ( 2921 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.32

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017994046).

BP6

Variant 4-87615883-A-G is Benign according to our data. Variant chr4-87615883-A-G is described in ClinVar as Benign. ClinVar VariationId is 402805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.3221A>G	p.Asp1074Gly	missense_variant	Exon 5 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1 link	n.367-47350T>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.3221A>G	p.Asp1074Gly	missense_variant	Exon 5 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

21853

AN:

119330

Hom.:

3104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0761

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.175

GnomAD2 exomes

AF:

0.0847

AC:

8635

AN:

102000

AF XY:

0.0801

show subpopulations

Gnomad AFR exome

AF:

0.0327

Gnomad AMR exome

AF:

0.0405

Gnomad ASJ exome

AF:

0.0300

Gnomad EAS exome

AF:

0.0715

Gnomad FIN exome

AF:

0.124

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.0969

GnomAD4 exome

AF:

0.0437

AC:

33655

AN:

769358

Hom.:

2921

Cov.:

155

AF XY:

0.0490

AC XY:

18727

AN XY:

382046

show subpopulations

African (AFR)

AF:

0.0140

AC:

373

AN:

26714

American (AMR)

AF:

0.0230

AC:

602

AN:

26194

Ashkenazi Jewish (ASJ)

AF:

0.0443

AC:

756

AN:

17054

East Asian (EAS)

AF:

0.0622

AC:

1524

AN:

24520

South Asian (SAS)

AF:

0.0361

AC:

1517

AN:

41988

European-Finnish (FIN)

AF:

0.113

AC:

3696

AN:

32682

Middle Eastern (MID)

AF:

0.0711

AC:

266

AN:

3740

European-Non Finnish (NFE)

AF:

0.0412

AC:

23149

AN:

562204

Other (OTH)

AF:

0.0517

AC:

1772

AN:

34262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

1586

3173

4759

6346

7932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.183

AC:

21872

AN:

119444

Hom.:

3113

Cov.:

AF XY:

0.179

AC XY:

10415

AN XY:

58054

show subpopulations

African (AFR)

AF:

0.0761

AC:

2482

AN:

32612

American (AMR)

AF:

0.158

AC:

1915

AN:

12104

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

514

AN:

3000

East Asian (EAS)

AF:

0.155

AC:

597

AN:

3844

South Asian (SAS)

AF:

0.225

AC:

812

AN:

3608

European-Finnish (FIN)

AF:

0.208

AC:

1594

AN:

7678

Middle Eastern (MID)

AF:

0.145

AC:

AN:

228

European-Non Finnish (NFE)

AF:

0.249

AC:

13450

AN:

53998

Other (OTH)

AF:

0.181

AC:

296

AN:

1632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

542

1084

1625

2167

2709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.242

Hom.:

1704

ExAC

AF:

0.107

AC:

2267

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.086

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0018

MetaSVM

Uncertain

-0.078

MutationAssessor

Benign

0.0

PhyloP100

2.3

PROVEAN

Benign

-0.87

REVEL

Benign

0.20

Sift4G

Benign

0.30

Vest4

0.34

ClinPred

0.015

GERP RS

1.5

Varity_R

0.19

gMVP

0.00070

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over