chr4-87612293-T-C

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.136-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,612,380 control chromosomes in the GnomAD database, including 67,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.23 ( 4421 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62912 hom. )

Consequence

DSPP
NM_014208.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.08

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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-87612293-T-C is Benign according to our data. Variant chr4-87612293-T-C is described in ClinVar as Benign. ClinVar VariationId is 260355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.136-29T>C		intron_variant	Intron 3 of 4	ENST00000651931.1	NP_055023.2	Q9NZW4
DMP1-AS1	NR_198971.1 link	n.367-43760A>G		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.136-29T>C		intron_variant	Intron 3 of 4		NM_014208.3	ENSP00000498766.1		Q9NZW4

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34397

AN:

151976

Hom.:

4413

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0964

Gnomad AMI

AF:

0.310

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.287

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.229

Gnomad NFE

AF:

0.301

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.252

AC:

62326

AN:

246932

AF XY:

0.262

show subpopulations

Gnomad AFR exome

AF:

0.0858

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.304

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.289

AC:

422695

AN:

1460286

Hom.:

62912

Cov.:

AF XY:

0.291

AC XY:

211044

AN XY:

726374

show subpopulations

African (AFR)

AF:

0.0867

AC:

2901

AN:

33462

American (AMR)

AF:

0.151

AC:

6749

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

5537

AN:

26118

East Asian (EAS)

AF:

0.222

AC:

8797

AN:

39648

South Asian (SAS)

AF:

0.294

AC:

25304

AN:

86110

European-Finnish (FIN)

AF:

0.277

AC:

14798

AN:

53340

Middle Eastern (MID)

AF:

0.241

AC:

1389

AN:

5768

European-Non Finnish (NFE)

AF:

0.307

AC:

340876

AN:

1110914

Other (OTH)

AF:

0.271

AC:

16344

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16583

33166

49749

66332

82915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11004

22008

33012

44016

55020

<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:

0.226

AC:

34412

AN:

152094

Hom.:

4421

Cov.:

AF XY:

0.223

AC XY:

16600

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0965

AC:

4005

AN:

41514

American (AMR)

AF:

0.200

AC:

3052

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

751

AN:

3472

East Asian (EAS)

AF:

0.207

AC:

1072

AN:

5168

South Asian (SAS)

AF:

0.286

AC:

1381

AN:

4822

European-Finnish (FIN)

AF:

0.269

AC:

2844

AN:

10576

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.301

AC:

20455

AN:

67954

Other (OTH)

AF:

0.240

AC:

505

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1328

2655

3983

5310

6638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.264

Hom.:

1519

Bravo

AF:

0.213

Asia WGS

AF:

0.276

AC:

960

AN:

3478

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.8

(source)

DANN

Benign

0.47

PhyloP100

-1.1

BranchPoint Hunter

2.0

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