chr4-87612913-G-A

Position:

chr4-87612913-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_014208.3(DSPP):c.727G>A(p.Asp243Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,614,080 control chromosomes in the GnomAD database, including 3,226 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.035 ( 391 hom., cov: 32)

Exomes 𝑓: 0.032 ( 2835 hom. )

Consequence

DSPP
NM_014208.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.40

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=0.008893698).

BP6

Variant 4-87612913-G-A is Benign according to our data. Variant chr4-87612913-G-A is described in ClinVar as [Benign]. Clinvar id is 197292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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.727G>A	p.Asp243Asn	missense_variant	4/5	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.727G>A	p.Asp243Asn	missense_variant	4/5		NM_014208.3	ENSP00000498766	P1
	ENST00000506480.5 linkuse as main transcript	n.323-44380C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0354

AC:

5391

AN:

152102

Hom.:

392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0224

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0253

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.0562

Gnomad FIN

AF:

0.0233

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0421

GnomAD3 exomes

AF:

0.0583

AC:

14549

AN:

249448

Hom.:

1523

AF XY:

0.0534

AC XY:

7230

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.0931

Gnomad ASJ exome

AF:

0.0280

Gnomad EAS exome

AF:

0.373

Gnomad SAS exome

AF:

0.0407

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.0179

Gnomad OTH exome

AF:

0.0446

GnomAD4 exome

AF:

0.0322

AC:

47120

AN:

1461860

Hom.:

2835

Cov.:

AF XY:

0.0318

AC XY:

23149

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0240

Gnomad4 AMR exome

AF:

0.0859

Gnomad4 ASJ exome

AF:

0.0258

Gnomad4 EAS exome

AF:

0.314

Gnomad4 SAS exome

AF:

0.0418

Gnomad4 FIN exome

AF:

0.0219

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0458

GnomAD4 genome

AF:

0.0355

AC:

5400

AN:

152220

Hom.:

391

Cov.:

AF XY:

0.0375

AC XY:

2790

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0225

Gnomad4 AMR

AF:

0.0413

Gnomad4 ASJ

AF:

0.0253

Gnomad4 EAS

AF:

0.357

Gnomad4 SAS

AF:

0.0553

Gnomad4 FIN

AF:

0.0233

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.0431

Alfa

AF:

0.0290

Hom.:

689

Bravo

AF:

0.0406

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.0227

AC:

ESP6500EA

AF:

0.0208

AC:

174

ExAC

AF:

0.0557

AC:

6742

Asia WGS

AF:

0.166

AC:

576

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27884173, 23018043, 18797159) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.098

Eigen

Benign

0.095

Eigen_PC

Benign

0.021

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0089

MetaSVM

Benign

-1.4

MutationAssessor

Benign

0.63

MutationTaster

Benign

0.93

P;P

PROVEAN

Benign

-0.94

REVEL

Uncertain

0.34

Sift4G

Benign

0.37

Polyphen

0.99

Vest4

0.099

ClinPred

0.033

GERP RS

3.7

Varity_R

0.17

gMVP

0.020

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