rs959216315

chr4-87616343-C-Achr4-87616343-C-Gchr4-87616343-C-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.3681C>A(p.Asp1227Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 127,194 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D1227D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (202 hom., cov: 32)
  • Exomes 𝑓: 0.011 (1115 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.44

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=0.0036220253).
• BP6: Variant 4-87616343-C-A is Benign according to our data. Variant chr4-87616343-C-A is described in ClinVar as [Benign]. Clinvar id is 523082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87616343-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.3681C>A	p.Asp1227Glu	missense_variant	5/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.3681C>A	p.Asp1227Glu	missense_variant	5/5		NM_014208.3	P1
	ENST00000506480.5	n.323-47810G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 5685 AN: 127092 Hom.: 201 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.00410

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0430

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0324

GnomAD3 exomes AF: 0.00545 AC: 796 AN: 146032 Hom.: 210 AF XY: 0.00481 AC XY: 374 AN XY: 77788

Gnomad AFR exome AF: 0.0949

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000965

Gnomad EAS exome AF: 0.000281

Gnomad SAS exome AF: 0.000772

Gnomad FIN exome AF: 0.00598

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00288

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0115 AC: 14402 AN: 1256910 Hom.: 1115 Cov.: 203 AF XY: 0.0120 AC XY: 7413 AN XY: 619838

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.00379

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0459

Gnomad4 NFE exome AF: 0.00737

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0448 AC: 5703 AN: 127194 Hom.: 202 Cov.: 32 AF XY: 0.0439 AC XY: 2735 AN XY: 62260

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.0322

Gnomad4 EAS AF: 0.00411

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0206

Gnomad4 OTH AF: 0.0320

Alfa AF: 0.0000315 Hom.: 0

ExAC AF: 0.0000427 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	- -

Deafness, autosomal dominant 39, with dentinogenesis imperfecta 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.042
Dann	Benign	0.66
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	0.50	N
REVEL	Benign	0.25
Sift4G	Benign	0.34	T
Polyphen		0.99	D
Vest4		0.091
MutPred		0.27		Gain of glycosylation at S1226 (P = 2e-04);
MVP		0.44
ClinPred		0.017	T
GERP RS		-1.5
Varity_R		0.057
gMVP		0.00026

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: rs959216315; hg19: chr4-88537495;