rs61731011

Positions:

chr4-87613246-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_014208.3(DSPP):c.1060C>T(p.Arg354Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,718 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R354H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0051 ( 36 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 1.97

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 -8 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=0.0036010146).

BP6

Variant 4-87613246-C-T is Benign according to our data. Variant chr4-87613246-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260354.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=2}. Variant chr4-87613246-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 562 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3 linkuse as main transcript	c.1060C>T	p.Arg354Cys	missense_variant	4/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1 linkuse as main transcript	c.1060C>T	p.Arg354Cys	missense_variant	4/5		NM_014208.3	P1
	ENST00000506480.5 linkuse as main transcript	n.323-44713G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

561

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00977

Gnomad FIN

AF:

0.00358

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00438

AC:

1080

AN:

246612

Hom.:

AF XY:

0.00461

AC XY:

620

AN XY:

134496

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00363

Gnomad ASJ exome

AF:

0.00180

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00811

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00433

GnomAD4 exome

AF:

0.00510

AC:

7451

AN:

1461540

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

3805

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00340

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.000882

Gnomad4 SAS exome

AF:

0.00864

Gnomad4 FIN exome

AF:

0.00320

Gnomad4 NFE exome

AF:

0.00538

Gnomad4 OTH exome

AF:

0.00437

GnomAD4 genome

AF:

0.00369

AC:

562

AN:

152178

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.00511

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00998

Gnomad4 FIN

AF:

0.00358

Gnomad4 NFE

AF:

0.00500

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00457

Hom.:

Bravo

AF:

0.00332

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000794

AC:

ESP6500EA

AF:

0.00464

AC:

ExAC

AF:

0.00441

AC:

532

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	DSPP: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 09, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.1060C>T (p.R354C) alteration is located in exon 4 (coding exon 3) of the DSPP gene. This alteration results from a C to T substitution at nucleotide position 1060, causing the arginine (R) at amino acid position 354 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 14, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.077

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

-0.40

REVEL

Benign

0.27

Sift4G

Uncertain

0.041

Polyphen

0.85

Vest4

0.12

MVP

0.70

ClinPred

0.011

GERP RS

1.3

Varity_R

0.13

gMVP

0.0076

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