rs36094464

chr4-87612388-A-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.202A>T(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,613,918 control chromosomes in the GnomAD database, including 7,604 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2520 hom., cov: 32)
  • Exomes 𝑓: 0.068 (5084 hom.)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: -0.106

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=0.010052949).
• BP6: Variant 4-87612388-A-T is Benign according to our data. Variant chr4-87612388-A-T is described in ClinVar as [Benign]. Clinvar id is 16858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87612388-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.202A>T	p.Arg68Trp	missense_variant	4/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.202A>T	p.Arg68Trp	missense_variant	4/5		NM_014208.3	P1
	ENST00000506480.5	n.323-43855T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21091 AN: 152042 Hom.: 2517 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0638

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0848 AC: 21119 AN: 249020 Hom.: 1541 AF XY: 0.0826 AC XY: 11151 AN XY: 135072

Gnomad AFR exome AF: 0.325

Gnomad AMR exome AF: 0.0438

Gnomad ASJ exome AF: 0.0910

Gnomad EAS exome AF: 0.0128

Gnomad SAS exome AF: 0.0684

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0768

GnomAD4 exome AF: 0.0685 AC: 100116 AN: 1461758 Hom.: 5084 Cov.: 82 AF XY: 0.0685 AC XY: 49814 AN XY: 727164

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.0467

Gnomad4 ASJ exome AF: 0.0906

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.0720

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.0583

Gnomad4 OTH exome AF: 0.0806

GnomAD4 genome AF: 0.139 AC: 21120 AN: 152160 Hom.: 2520 Cov.: 32 AF XY: 0.139 AC XY: 10374 AN XY: 74398

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.0636

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.0740

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0755 Hom.: 451

Bravo AF: 0.139

TwinsUK AF: 0.0585 AC: 217

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.309 AC: 1194

ESP6500EA AF: 0.0647 AC: 537

ExAC AF: 0.0903 AC: 10915

Asia WGS AF: 0.0510 AC: 179 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0654

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2018	This variant is associated with the following publications: (PMID: 15592686, 22521702, 19103209, 16955410, 17026502, 17627120, 14758537, 27884173, 20981092, 22310900, 18797159) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Dentinogenesis imperfecta type 2 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 15, 2016

- -

DSPP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift4G	Uncertain	0.0040	D
Polyphen		0.14	B
Vest4		0.22
ClinPred		0.0056	T
GERP RS		-2.3
Varity_R		0.27
gMVP		0.19

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: rs36094464; hg19: chr4-88533540; COSMIC: COSV56810257;