rs2736982

Positions:

• chr4-87613083-A-G
• chr4-87613083-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014208.3(DSPP):​c.897A>G​(p.Ser299Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,613,822 control chromosomes in the GnomAD database, including 307,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32065 hom., cov: 31)
  • Exomes 𝑓: 0.61 (275002 hom.)
• Consequence: DSPP NM_014208.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0520

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]

ENSG00000249001 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-87613083-A-G is Benign according to our data. Variant chr4-87613083-A-G is described in ClinVar as [Benign]. Clinvar id is 260359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87613083-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSPP	NM_014208.3	c.897A>G	p.Ser299Ser	synonymous_variant	4/5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.897A>G	p.Ser299Ser	synonymous_variant	4/5		NM_014208.3	ENSP00000498766.1
ENSG00000249001	ENST00000506480.5	n.323-44550T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98294 AN: 151874 Hom.: 32012 Cov.: 31

Gnomad AFR AF: 0.729

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.640

GnomAD3 exomes AF: 0.626 AC: 156098 AN: 249262 Hom.: 49297 AF XY: 0.621 AC XY: 84038 AN XY: 135246

Gnomad AFR exome AF: 0.733

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.691

Gnomad SAS exome AF: 0.578

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.614

Gnomad OTH exome AF: 0.625

GnomAD4 exome AF: 0.612 AC: 894895 AN: 1461830 Hom.: 275002 Cov.: 81 AF XY: 0.611 AC XY: 444299 AN XY: 727210

Gnomad4 AFR exome AF: 0.741

Gnomad4 AMR exome AF: 0.603

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.578

Gnomad4 FIN exome AF: 0.681

Gnomad4 NFE exome AF: 0.607

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.647 AC: 98399 AN: 151992 Hom.: 32065 Cov.: 31 AF XY: 0.646 AC XY: 48024 AN XY: 74290

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.583

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.586

Gnomad4 FIN AF: 0.680

Gnomad4 NFE AF: 0.614

Gnomad4 OTH AF: 0.645

Alfa AF: 0.615 Hom.: 68540

Bravo AF: 0.647

Asia WGS AF: 0.659 AC: 2294 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.604

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Dentinogenesis imperfecta type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Denticles Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Dentinogenesis imperfecta type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.76
DANN	Benign	0.53

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

Other links and lift over

dbSNP: rs2736982; hg19: chr4-88534235; COSMIC: COSV56810948;