rs36094464

Positions:

chr4-87612388-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014208.3(DSPP):c.202A>T(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,918 control chromosomes in the GnomAD database, including 7,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2520 hom., cov: 32)

Exomes 𝑓: 0.068 ( 5084 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: -0.106

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:

ENSG00000249001 (HGNC:58144):

ENSG00000249001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010052949).

BP6

Variant 4-87612388-A-T is Benign according to our data. Variant chr4-87612388-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 16858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87612388-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSPP	NM_014208.3 link	c.202A>T	p.Arg68Trp	missense_variant	4/5	ENST00000651931.1	NP_055023.2	Q9NZW4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1 link	c.202A>T	p.Arg68Trp	missense_variant	4/5		NM_014208.3	ENSP00000498766.1		Q9NZW4
ENSG00000249001	ENST00000506480.5 link	n.323-43855T>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21091

AN:

152042

Hom.:

2517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.319

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0638

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0646

Gnomad OTH

AF:

0.110

GnomAD3 exomes

AF:

0.0848

AC:

21119

AN:

249020

Hom.:

1541

AF XY:

0.0826

AC XY:

11151

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.325

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.0910

Gnomad EAS exome

AF:

0.0128

Gnomad SAS exome

AF:

0.0684

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0768

GnomAD4 exome

AF:

0.0685

AC:

100116

AN:

1461758

Hom.:

5084

Cov.:

AF XY:

0.0685

AC XY:

49814

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.328

Gnomad4 AMR exome

AF:

0.0467

Gnomad4 ASJ exome

AF:

0.0906

Gnomad4 EAS exome

AF:

0.0105

Gnomad4 SAS exome

AF:

0.0720

Gnomad4 FIN exome

AF:

0.145

Gnomad4 NFE exome

AF:

0.0583

Gnomad4 OTH exome

AF:

0.0806

GnomAD4 genome

AF:

0.139

AC:

21120

AN:

152160

Hom.:

2520

Cov.:

AF XY:

0.139

AC XY:

10374

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.319

Gnomad4 AMR

AF:

0.0636

Gnomad4 ASJ

AF:

0.0862

Gnomad4 EAS

AF:

0.0114

Gnomad4 SAS

AF:

0.0740

Gnomad4 FIN

AF:

0.146

Gnomad4 NFE

AF:

0.0646

Gnomad4 OTH

AF:

0.109

Alfa

AF:

0.0755

Hom.:

451

Bravo

AF:

0.139

TwinsUK

AF:

0.0585

AC:

217

ALSPAC

AF:

0.0501

AC:

193

ESP6500AA

AF:

0.309

AC:

1194

ESP6500EA

AF:

0.0647

AC:

537

ExAC

AF:

0.0903

AC:

10915

Asia WGS

AF:

0.0510

AC:

179

AN:

3478

EpiCase

AF:

0.0638

EpiControl

AF:

0.0654

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2018	This variant is associated with the following publications: (PMID: 15592686, 22521702, 19103209, 16955410, 17026502, 17627120, 14758537, 27884173, 20981092, 22310900, 18797159) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Dentinogenesis imperfecta type 2

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2016

- -

DSPP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.59

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift4G

Uncertain

0.0040

Polyphen

0.14

Vest4

0.22

ClinPred

0.0056

GERP RS

-2.3

Varity_R

0.27

gMVP

0.19

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