4-87610957-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.49C>T​(p.Pro17Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on 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. P17L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSPP
NM_014208.3 missense, splice_region

Scores

4
8
5
Splicing: ADA: 0.9948
1
1

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, 0.79
PP5
Variant 4-87610957-C-T is Pathogenic according to our data. Variant chr4-87610957-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1458861.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-87610957-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPPNM_014208.3 linkc.49C>T p.Pro17Ser 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.49C>T p.Pro17Ser missense_variant, splice_region_variant Exon 2 of 5 NM_014208.3 ENSP00000498766.1 Q9NZW4
ENSG00000249001ENST00000506480.5 linkn.323-42424G>A intron_variant Intron 3 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249370
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135284
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461168
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726934
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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
Feb 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 17 of the DSPP protein (p.Pro17Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with dentinogenesis imperfecta (PMID: 17686168, 18521831; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1458861). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.079
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Uncertain
2.0
M
PROVEAN
Benign
-1.9
N
REVEL
Uncertain
0.60
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.69
MutPred
0.53
Loss of catalytic residue at P17 (P = 0.0265);
MVP
0.89
ClinPred
0.80
D
GERP RS
4.9
Varity_R
0.46
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Benign
0.63
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912986; hg19: chr4-88532109; API