rs762157486

Positions:

• chr4-87615677-TAGCAGTGAC-T
• chr4-87615677-TAGCAGTGAC-TAGCAGTGACAGCAGTGAC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 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

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 Likely_benign. Variant got -3 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 id is 445476.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 521 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSPP	NM_014208.3	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	5/5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.3033_3041delCAGCAGTGA	p.Ser1012_Asp1014del	disruptive_inframe_deletion	5/5		NM_014208.3	ENSP00000498766.1
ENSG00000249001	ENST00000506480.5	n.323-47153_323-47145delGTCACTGCT		intron_variant		3

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

GnomAD3 exomes AF: 0.00359 AC: 545 AN: 151648 Hom.: 5 AF XY: 0.00382 AC XY: 307 AN XY: 80418

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 SAS exome AF: 0.00391

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

Gnomad4 AFR exome AF: 0.000862

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.000325

Gnomad4 EAS exome AF: 0.00251

Gnomad4 SAS exome AF: 0.00439

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00702

Gnomad4 OTH exome AF: 0.00443

GnomAD4 genome AF: 0.00372 AC: 521 AN: 140010 Hom.: 3 Cov.: 33 AF XY: 0.00351 AC XY: 240 AN XY: 68422

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00174

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00177

Gnomad4 SAS AF: 0.00400

Gnomad4 FIN AF: 0.00215

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00556

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DSPP: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs762157486; hg19: chr4-88536829;