rs3750025

chr4-87612913-G-Achr4-87612913-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_014208.3(DSPP):c.727G>A(p.Asp243Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 1,614,080 control chromosomes in the GnomAD database, including 3,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (391 hom., cov: 32)
  • Exomes 𝑓: 0.032 (2835 hom.)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.40

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DSPP
• BP4: Computational evidence support a benign effect (MetaRNN=0.008893698).
• BP6: Variant 4-87612913-G-A is Benign according to our data. Variant chr4-87612913-G-A is described in ClinVar as [Benign]. Clinvar id is 197292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.727G>A	p.Asp243Asn	missense_variant	4/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.727G>A	p.Asp243Asn	missense_variant	4/5		NM_014208.3	P1
	ENST00000506480.5	n.323-44380C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5391 AN: 152102 Hom.: 392 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.0562

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0583 AC: 14549 AN: 249448 Hom.: 1523 AF XY: 0.0534 AC XY: 7230 AN XY: 135342

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.373

Gnomad SAS exome AF: 0.0407

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0446

GnomAD4 exome AF: 0.0322 AC: 47120 AN: 1461860 Hom.: 2835 Cov.: 84 AF XY: 0.0318 AC XY: 23149 AN XY: 727222

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.0859

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.0418

Gnomad4 FIN exome AF: 0.0219

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.0355 AC: 5400 AN: 152220 Hom.: 391 Cov.: 32 AF XY: 0.0375 AC XY: 2790 AN XY: 74430

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.0413

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0290 Hom.: 689

Bravo AF: 0.0406

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0215 AC: 83

ESP6500AA AF: 0.0227 AC: 93

ESP6500EA AF: 0.0208 AC: 174

ExAC AF: 0.0557 AC: 6742

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27884173, 23018043, 18797159) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Benign	0.89
DEOGEN2	Benign	0.098	T
Eigen	Benign	0.095
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.4	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	0.93	P;P
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.34
Sift4G	Benign	0.37	T
Polyphen		0.99	D
Vest4		0.099
ClinPred		0.033	T
GERP RS		3.7
Varity_R		0.17
gMVP		0.020

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

LitVar

Other links and lift over

dbSNP: rs3750025; hg19: chr4-88534065; COSMIC: COSV56808885;