4-87610918-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_014208.3(DSPP):c.10A>C(p.Ile4Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.325

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a signal_peptide (size 14) in uniprot entity DSPP_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014208.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DSPP
• BP4: Computational evidence support a benign effect (MetaRNN=0.3654663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.10A>C	p.Ile4Leu	missense_variant	2/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.10A>C	p.Ile4Leu	missense_variant	2/5		NM_014208.3	P1
	ENST00000506480.5	n.323-42385T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with DSPP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the DSPP protein (p.Ile4Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.092	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.99	N;N
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.36
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.21		Loss of methylation at K2 (P = 0.0475);
MVP		0.72
ClinPred		0.76	D
GERP RS		3.7
Varity_R		0.33
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr4-88532070;