4-87615677-TAGCAGTGAC-T

Variant names:

• chr4-87615677-TAGCAGTGAC-T
• rs762157486
• NM_014208.3:c.3033_3041delCAGCAGTGA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_014208.3(DSPP):​c.3033_3041delCAGCAGTGA​(p.Ser1012_Asp1014del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,520,544 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (37 hom.)
• Consequence: DSPP NM_014208.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.20
• Publications: 0 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• dentinogenesis imperfecta

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• 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

ENSG00000249001 (HGNC:58144):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014208.3.
• BP6: Variant 4-87615677-TAGCAGTGAC-T is Benign according to our data. Variant chr4-87615677-TAGCAGTGAC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445476.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (521/140010) while in subpopulation NFE AF = 0.00601 (393/65368). AF 95% confidence interval is 0.00552. There are 3 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 521 AD,Unknown gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	NM_014208.3	MANE Select	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	Exon 5 of 5	NP_055023.2
	DMP1-AS1	NR_198971.1		n.367-47153_367-47145delGTCACTGCT		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	ENST00000651931.1	MANE Select	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000498766.1
	ENSG00000249001	ENST00000506480.5	TSL:3	n.323-47153_323-47145delGTCACTGCT		intron	N/A
	ENSG00000249001	ENST00000829286.1		n.357-47153_357-47145delGTCACTGCT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 520 AN: 139900 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.00399

Gnomad FIN AF: 0.00215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00564

GnomAD2 exomes AF: 0.00359 AC: 545 AN: 151648 AF XY: 0.00382

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00175

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00371

GnomAD4 exome AF: 0.00606 AC: 8368 AN: 1380534 Hom.: 37 AF XY: 0.00610 AC XY: 4152 AN XY: 680344

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

African (AFR) AF: 0.000862 AC: 26 AN: 30172

American (AMR) AF: 0.00242 AC: 83 AN: 34334

Ashkenazi Jewish (ASJ) AF: 0.000325 AC: 8 AN: 24616

East Asian (EAS) AF: 0.00251 AC: 87 AN: 34600

South Asian (SAS) AF: 0.00439 AC: 339 AN: 77198

European-Finnish (FIN) AF: 0.00135 AC: 65 AN: 48294

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5554

European-Non Finnish (NFE) AF: 0.00702 AC: 7505 AN: 1068920

Other (OTH) AF: 0.00443 AC: 252 AN: 56846

⚠️ 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: 0.00372 AC: 521 AN: 140010 Hom.: 3 Cov.: 33 AF XY: 0.00351 AC XY: 240 AN XY: 68422

African (AFR) AF: 0.00132 AC: 47 AN: 35730

American (AMR) AF: 0.00174 AC: 25 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.00177 AC: 8 AN: 4524

South Asian (SAS) AF: 0.00400 AC: 17 AN: 4254

European-Finnish (FIN) AF: 0.00215 AC: 20 AN: 9324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00601 AC: 393 AN: 65368

Other (OTH) AF: 0.00556 AC: 11 AN: 1978

Alfa AF: 0.000246 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DSPP: BS2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=199/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs762157486; hg19: chr4-88536829;