4-87610958-C-T

Variant names:

• chr4-87610958-C-T
• NM_014208.3:c.50C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_014208.3(DSPP):​c.50C>T​(p.Pro17Leu) variant causes a missense, 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P17S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSPP NM_014208.3 missense, splice_region
• Scores: Splicing: ADA: 0.9620
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.56

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:58144):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 4-87610958-C-T is Pathogenic according to our data. Variant chr4-87610958-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2734658.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-87610958-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3	c.50C>T	p.Pro17Leu	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.50C>T	p.Pro17Leu	missense_variant, splice_region_variant	Exon 2 of 5		NM_014208.3	ENSP00000498766.1
ENSG00000249001	ENST00000506480.5	n.323-42425G>A		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individuals with dentinogenesis imperfecta (PMID: 22243242, 22310900). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 17 of the DSPP protein (p.Pro17Leu). This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Pro17 amino acid residue in DSPP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17686168, 18521831). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.0	M
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.70
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.53		Loss of glycosylation at S21 (P = 0.0291);
MVP		0.93
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.51
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88532110;