rs762157486

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_014208.3(DSPP):c.3033_3041delCAGCAGTGA(p.Ser1012_Asp1014del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,520,544 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 37 hom. )

Consequence

DSPP
NM_014208.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.20

Publications

0 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 -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_014208.3.

BP6

Variant 4-87615677-TAGCAGTGAC-T is Benign according to our data. Variant chr4-87615677-TAGCAGTGAC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445476.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (521/140010) while in subpopulation NFE AF = 0.00601 (393/65368). AF 95% confidence interval is 0.00552. There are 3 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 521 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	Exon 5 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1 link	n.367-47153_367-47145delGTCACTGCT		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	Exon 5 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes

AF:

0.00372

AC:

520

AN:

139900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00174

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00176

Gnomad SAS

AF:

0.00399

Gnomad FIN

AF:

0.00215

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00601

Gnomad OTH

AF:

0.00564

GnomAD2 exomes

AF:

0.00359

AC:

545

AN:

151648

AF XY:

0.00382

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.00619

Gnomad OTH exome

AF:

0.00371

GnomAD4 exome

AF:

0.00606

AC:

8368

AN:

1380534

Hom.:

AF XY:

0.00610

AC XY:

4152

AN XY:

680344

show subpopulations

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

African (AFR)

AF:

0.000862

AC:

AN:

30172

American (AMR)

AF:

0.00242

AC:

AN:

34334

Ashkenazi Jewish (ASJ)

AF:

0.000325

AC:

AN:

24616

East Asian (EAS)

AF:

0.00251

AC:

AN:

34600

South Asian (SAS)

AF:

0.00439

AC:

339

AN:

77198

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

48294

Middle Eastern (MID)

AF:

0.000540

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00702

AC:

7505

AN:

1068920

Other (OTH)

AF:

0.00443

AC:

252

AN:

56846

⚠️ 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: 0.399

Heterozygous variant carriers

605

1210

1816

2421

3026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.00372

AC:

521

AN:

140010

Hom.:

Cov.:

AF XY:

0.00351

AC XY:

240

AN XY:

68422

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

35730

American (AMR)

AF:

0.00174

AC:

AN:

14370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3366

East Asian (EAS)

AF:

0.00177

AC:

AN:

4524

South Asian (SAS)

AF:

0.00400

AC:

AN:

4254

European-Finnish (FIN)

AF:

0.00215

AC:

AN:

9324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00601

AC:

393

AN:

65368

Other (OTH)

AF:

0.00556

AC:

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000246

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Jun 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DSPP: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=199/1

polymorphism

(source)

Splicing

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