chr4-87612011-TTG-T

Variant names:

• chr4-87612011-TTG-T
• rs36228864
• NM_014208.3:c.52-65_52-64delTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014208.3(DSPP):​c.52-65_52-64delTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,039,370 control chromosomes in the GnomAD database, including 1,075 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.076 (940 hom., cov: 0)
  • Exomes 𝑓: 0.042 (135 hom.)
• Consequence: DSPP NM_014208.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.232
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 4-87612011-TTG-T is Benign according to our data. Variant chr4-87612011-TTG-T is described in ClinVar as Benign. ClinVar VariationId is 1272159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.207 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.52-65_52-64delTG		intron	N/A	NP_055023.2	Q9NZW4
	DMP1-AS1	NR_198971.1		n.367-43480_367-43479delCA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	ENST00000651931.1	MANE Select	c.52-93_52-92delTG		intron	N/A	ENSP00000498766.1	Q9NZW4
	DMP1-AS1	ENST00000506480.5	TSL:3	n.323-43480_323-43479delCA		intron	N/A
	DMP1-AS1	ENST00000829286.1		n.357-43480_357-43479delCA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0756 AC: 11321 AN: 149844 Hom.: 942 Cov.: 0

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0113

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.0287

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0656

GnomAD4 exome AF: 0.0419 AC: 37281 AN: 889418 Hom.: 135 AF XY: 0.0413 AC XY: 18860 AN XY: 457012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.222 AC: 4493 AN: 20222

American (AMR) AF: 0.0510 AC: 1774 AN: 34808

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 1353 AN: 20754

East Asian (EAS) AF: 0.0531 AC: 1705 AN: 32120

South Asian (SAS) AF: 0.0334 AC: 2132 AN: 63876

European-Finnish (FIN) AF: 0.0467 AC: 2189 AN: 46828

Middle Eastern (MID) AF: 0.0562 AC: 174 AN: 3098

European-Non Finnish (NFE) AF: 0.0340 AC: 21333 AN: 627560

Other (OTH) AF: 0.0530 AC: 2128 AN: 40152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0756 AC: 11341 AN: 149952 Hom.: 940 Cov.: 0 AF XY: 0.0744 AC XY: 5443 AN XY: 73174

African (AFR) AF: 0.211 AC: 8619 AN: 40810

American (AMR) AF: 0.0357 AC: 538 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 160 AN: 3448

East Asian (EAS) AF: 0.0288 AC: 145 AN: 5038

South Asian (SAS) AF: 0.0114 AC: 54 AN: 4722

European-Finnish (FIN) AF: 0.0324 AC: 334 AN: 10324

Middle Eastern (MID) AF: 0.0759 AC: 22 AN: 290

European-Non Finnish (NFE) AF: 0.0197 AC: 1325 AN: 67282

Other (OTH) AF: 0.0644 AC: 134 AN: 2080

Alfa AF: 0.0259 Hom.: 615

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs36228864; hg19: chr4-88533163; COSMIC: COSV106054070;