rs2627699

Variant names:

• chr4-87610648-C-T
• rs2627699
• NM_014208.3:c.-28-233C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014208.3(DSPP):​c.-28-233C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,986 control chromosomes in the GnomAD database, including 6,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.27 (6145 hom., cov: 32)
• Consequence: DSPP NM_014208.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.402
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dentinogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dentinogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• dentinogenesis imperfecta type 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dentin dysplasia type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DMP1-AS1 (HGNC:58144):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-87610648-C-T is Benign according to our data. Variant chr4-87610648-C-T is described in ClinVar as Benign. ClinVar VariationId is 1179349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	NM_014208.3	MANE Select	c.-28-233C>T		intron	N/A	NP_055023.2	Q9NZW4
	DMP1-AS1	NR_198971.1		n.367-42115G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	ENST00000651931.1	MANE Select	c.-28-233C>T		intron	N/A	ENSP00000498766.1	Q9NZW4
	DMP1-AS1	ENST00000506480.5	TSL:3	n.323-42115G>A		intron	N/A
	DMP1-AS1	ENST00000829286.1		n.357-42115G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40547 AN: 151868 Hom.: 6135 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.276

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.267 AC: 40575 AN: 151986 Hom.: 6145 Cov.: 32 AF XY: 0.266 AC XY: 19749 AN XY: 74304

African (AFR) AF: 0.135 AC: 5617 AN: 41472

American (AMR) AF: 0.243 AC: 3705 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 838 AN: 3470

East Asian (EAS) AF: 0.569 AC: 2938 AN: 5160

South Asian (SAS) AF: 0.342 AC: 1647 AN: 4814

European-Finnish (FIN) AF: 0.294 AC: 3105 AN: 10554

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21768 AN: 67946

Other (OTH) AF: 0.284 AC: 598 AN: 2106

Alfa AF: 0.270 Hom.: 1091

Bravo AF: 0.259

Asia WGS AF: 0.445 AC: 1545 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.3
DANN	Benign	0.61
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2627699; hg19: chr4-88531800; COSMIC: COSV56817082; COSMIC: COSV56817082;