4-87610958-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_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

6
7
4
Splicing: ADA: 0.9620
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.56
Variant links:
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]

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ACMG classification

Classification made for transcript

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
MetaRNN computational evidence supports a deleterious effect, 0.818
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
DSPPNM_014208.3 linkc.50C>T p.Pro17Leu missense_variant, splice_region_variant Exon 2 of 5 ENST00000651931.1 NP_055023.2 Q9NZW4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPPENST00000651931.1 linkc.50C>T p.Pro17Leu missense_variant, splice_region_variant Exon 2 of 5 NM_014208.3 ENSP00000498766.1 Q9NZW4
ENSG00000249001ENST00000506480.5 linkn.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
LINK: link

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; API