rs121912989

Positions:

• chr4-87610952-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_014208.3(DSPP):​c.44C>T​(p.Ala15Val) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSPP. . Trascript score misZ 3.203 (greater than threshold 3.09). GenCC has associacion of gene with dentin dysplasia type I, dentinogenesis imperfecta, deafness, autosomal dominant 39, with dentinogenesis imperfecta 1, dentin dysplasia type II, dentinogenesis imperfecta type 2, dentinogenesis imperfecta type 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786
• PP5: Variant 4-87610952-C-T is Pathogenic according to our data. Variant chr4-87610952-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16859.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-87610952-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSPP	NM_014208.3	c.44C>T	p.Ala15Val	missense_variant	2/5	ENST00000651931.1	NP_055023.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.44C>T	p.Ala15Val	missense_variant	2/5		NM_014208.3	ENSP00000498766	P1
	ENST00000506480.5	n.323-42419G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Dentinogenesis imperfecta type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.46	A;A
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.46
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.31		Loss of disorder (P = 0.1546);
MVP		0.87
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.37
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs121912989; hg19: chr4-88532104; COSMIC: COSV56817021;