chr4-87612186-C-T

Variant names:

• chr4-87612186-C-T
• rs121912985
• NM_014208.3:c.133C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_014208.3(DSPP):​c.133C>T​(p.Gln45*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q45Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSPP NM_014208.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.47
• Publications: 17 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-87612186-C-T is Pathogenic according to our data. Variant chr4-87612186-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16853.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3	c.133C>T	p.Gln45*	stop_gained, splice_region_variant	Exon 3 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1	n.367-43653G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.133C>T	p.Gln45*	stop_gained, splice_region_variant	Exon 3 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.000107 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dentinogenesis imperfecta type 2 Pathogenic:1

Feb 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.5
Vest4		0.82
GERP RS		4.0
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
Splicevardb		2.0
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: 2

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

Other links and lift over

dbSNP: rs121912985; hg19: chr4-88533338;