4-87615883-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014208.3(DSPP):c.3221A>T(p.Asp1074Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 120,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1074G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000083 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0024 ( 485 hom. )

Failed GnomAD Quality Control

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33864444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.3221A>T	p.Asp1074Val	missense_variant	Exon 5 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1 link	n.367-47350T>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.3221A>T	p.Asp1074Val	missense_variant	Exon 5 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes

AF:

0.00000833

AC:

AN:

120060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00238

AC:

1832

AN:

769970

Hom.:

485

Cov.:

155

AF XY:

0.00253

AC XY:

967

AN XY:

382338

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

26714

American (AMR)

AF:

0.00111

AC:

AN:

26202

Ashkenazi Jewish (ASJ)

AF:

0.00217

AC:

AN:

17060

East Asian (EAS)

AF:

0.00582

AC:

143

AN:

24572

South Asian (SAS)

AF:

0.000190

AC:

AN:

42042

European-Finnish (FIN)

AF:

0.00403

AC:

132

AN:

32744

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

3746

European-Non Finnish (NFE)

AF:

0.00242

AC:

1362

AN:

562586

Other (OTH)

AF:

0.00289

AC:

AN:

34304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00000833

AC:

AN:

120060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

58292

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32604

American (AMR)

AF:

0.00

AC:

AN:

12156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3016

East Asian (EAS)

AF:

0.00

AC:

AN:

3882

South Asian (SAS)

AF:

0.00

AC:

AN:

3646

European-Finnish (FIN)

AF:

0.000129

AC:

AN:

7752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

54380

Other (OTH)

AF:

0.00

AC:

AN:

1628

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.10

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.0

PhyloP100

2.3

PROVEAN

Benign

-2.0

REVEL

Benign

0.26

Sift4G

Benign

0.22

Polyphen

0.99

Vest4

0.41

MutPred

0.25

Gain of glycosylation at S1070 (P = 4e-04);

MVP

0.87

ClinPred

0.16

GERP RS

1.5

Varity_R

0.38

gMVP

0.0013

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over