rs202210195

Positions:

• chr4-87615883-A-G
• chr4-87615883-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.3221A>G​(p.Asp1074Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 888,802 control chromosomes in the GnomAD database, including 6,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1074A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3113 hom., cov: 24)
  • Exomes 𝑓: 0.044 (2921 hom.)
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.32

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017994046).
• BP6: Variant 4-87615883-A-G is Benign according to our data. Variant chr4-87615883-A-G is described in ClinVar as [Benign]. Clinvar id is 402805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.3221A>G	p.Asp1074Gly	missense_variant	5/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.3221A>G	p.Asp1074Gly	missense_variant	5/5		NM_014208.3	P1
	ENST00000506480.5	n.323-47350T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 21853 AN: 119330 Hom.: 3104 Cov.: 24

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.0847 AC: 8635 AN: 102000 Hom.: 1053 AF XY: 0.0801 AC XY: 4192 AN XY: 52344

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.0715

Gnomad SAS exome AF: 0.0633

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.0437 AC: 33655 AN: 769358 Hom.: 2921 Cov.: 155 AF XY: 0.0490 AC XY: 18727 AN XY: 382046

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0230

Gnomad4 ASJ exome AF: 0.0443

Gnomad4 EAS exome AF: 0.0622

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0412

Gnomad4 OTH exome AF: 0.0517

GnomAD4 genome AF: 0.183 AC: 21872 AN: 119444 Hom.: 3113 Cov.: 24 AF XY: 0.179 AC XY: 10415 AN XY: 58054

Gnomad4 AFR AF: 0.0761

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.208

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.181

Alfa AF: 0.242 Hom.: 1704

ExAC AF: 0.107 AC: 2267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0018	T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.20
Sift4G	Benign	0.30	T
Polyphen		0.98	D
Vest4		0.34
ClinPred		0.015	T
GERP RS		1.5
Varity_R		0.19
gMVP		0.00070

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: rs202210195; hg19: chr4-88537035; COSMIC: COSV56807552;