rs202210195

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 14/18 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. D1074AAATAVIAVTAV?) has been classified as Likely benign.

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

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSPP. . Trascript score misZ 3.203 (greater than threshold 3.09). GenCC has associacion of gene with dentin dysplasia type I, dentinogenesis imperfecta, deafness, autosomal dominant 39, with dentinogenesis imperfecta 1, dentin dysplasia type II, dentinogenesis imperfecta type 2, dentinogenesis imperfecta type 3.

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 id 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/exons	MANE	Protein	UniProt
DSPP	NM_014208.3 linkuse as main transcript	c.3221A>G	p.Asp1074Gly	missense_variant	5/5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 linkuse as main transcript	c.3221A>G	p.Asp1074Gly	missense_variant	5/5		NM_014208.3	ENSP00000498766	P1
	ENST00000506480.5 linkuse as main transcript	n.323-47350T>C		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes

AF:

0.0847

AC:

8635

AN:

102000

Hom.:

1053

AF XY:

0.0801

AC XY:

4192

AN XY:

52344

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 SAS exome

AF:

0.0633

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

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.0230

Gnomad4 ASJ exome

AF:

0.0443

Gnomad4 EAS exome

AF:

0.0622

Gnomad4 SAS exome

AF:

0.0361

Gnomad4 FIN exome

AF:

0.113

Gnomad4 NFE exome

AF:

0.0412

Gnomad4 OTH exome

AF:

0.0517

GnomAD4 genome

AF:

0.183

AC:

21872

AN:

119444

Hom.:

3113

Cov.:

AF XY:

0.179

AC XY:

10415

AN XY:

58054

show subpopulations

Gnomad4 AFR

AF:

0.0761

Gnomad4 AMR

AF:

0.158

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.155

Gnomad4 SAS

AF:

0.225

Gnomad4 FIN

AF:

0.208

Gnomad4 NFE

AF:

0.249

Gnomad4 OTH

AF:

0.181

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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

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

MutationTaster

Benign

1.0

P;P

PROVEAN

Benign

-0.87

REVEL

Benign

0.20

Sift4G

Benign

0.30

Polyphen

0.98

Vest4

0.34

ClinPred

0.015

GERP RS

1.5

Varity_R

0.19

gMVP

0.00070

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over