rs2615489

Positions:

• chr4-87616585-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014208.3(DSPP):​c.*17G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,551,650 control chromosomes in the GnomAD database, including 579,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58082 hom., cov: 33)
  • Exomes 𝑓: 0.86 (521061 hom.)
• Consequence: DSPP NM_014208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.201

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-87616585-G-A is Benign according to our data. Variant chr4-87616585-G-A is described in ClinVar as [Benign]. Clinvar id is 260353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87616585-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSPP	NM_014208.3	c.*17G>A		3_prime_UTR_variant	5/5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.*17G>A		3_prime_UTR_variant	5/5		NM_014208.3	ENSP00000498766	P1
	ENST00000506480.5	n.323-48052C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132705 AN: 152158 Hom.: 58018 Cov.: 33

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.871

GnomAD3 exomes AF: 0.850 AC: 131246 AN: 154370 Hom.: 56271 AF XY: 0.838 AC XY: 68436 AN XY: 81704

Gnomad AFR exome AF: 0.896

Gnomad AMR exome AF: 0.929

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.888

Gnomad SAS exome AF: 0.712

Gnomad FIN exome AF: 0.886

Gnomad NFE exome AF: 0.864

Gnomad OTH exome AF: 0.847

GnomAD4 exome AF: 0.862 AC: 1205653 AN: 1399374 Hom.: 521061 Cov.: 80 AF XY: 0.856 AC XY: 590847 AN XY: 690188

Gnomad4 AFR exome AF: 0.896

Gnomad4 AMR exome AF: 0.923

Gnomad4 ASJ exome AF: 0.743

Gnomad4 EAS exome AF: 0.846

Gnomad4 SAS exome AF: 0.717

Gnomad4 FIN exome AF: 0.881

Gnomad4 NFE exome AF: 0.872

Gnomad4 OTH exome AF: 0.854

GnomAD4 genome AF: 0.872 AC: 132827 AN: 152276 Hom.: 58082 Cov.: 33 AF XY: 0.870 AC XY: 64753 AN XY: 74456

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.899

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.877

Gnomad4 SAS AF: 0.718

Gnomad4 FIN AF: 0.884

Gnomad4 NFE AF: 0.868

Gnomad4 OTH AF: 0.874

Alfa AF: 0.860 Hom.: 58270

Bravo AF: 0.877

Asia WGS AF: 0.819 AC: 2847 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.91
CADD	Benign	0.71
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2615489; hg19: chr4-88537737;