4-87616343-C-G

Variant names:

• chr4-87616343-C-G
• rs959216315
• NM_014208.3:c.3681C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014208.3(DSPP):​c.3681C>G​(p.Asp1227Glu) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1227D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DSPP NM_014208.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 1 publications found

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]

DSPP Gene-Disease associations (from GenCC):

• deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

  Inheritance: AD, Unknown Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• dentinogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dentinogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• dentinogenesis imperfecta type 3

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• dentin dysplasia type I

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dentin dysplasia type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000249001 (HGNC:58144):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07790342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSPP	NM_014208.3	c.3681C>G	p.Asp1227Glu	missense_variant	Exon 5 of 5	ENST00000651931.1	NP_055023.2
DMP1-AS1	NR_198971.1	n.367-47810G>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSPP	ENST00000651931.1	c.3681C>G	p.Asp1227Glu	missense_variant	Exon 5 of 5		NM_014208.3	ENSP00000498766.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 133510 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000685 AC: 1 AN: 146032 AF XY: 0.00

Gnomad AFR exome AF: 0.000177

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 203

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 133624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 65230

African (AFR) AF: 0.00 AC: 0 AN: 31012

American (AMR) AF: 0.00 AC: 0 AN: 14092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3358

East Asian (EAS) AF: 0.00 AC: 0 AN: 4896

South Asian (SAS) AF: 0.00 AC: 0 AN: 4320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63472

Other (OTH) AF: 0.00 AC: 0 AN: 1894

ExAC AF: 0.0000427 AC: 1

ClinVar

Not reported in ClinVar

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	0.045
DANN	Benign	0.50
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.4
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		0.060	T
GERP RS		-1.5
Varity_R		0.057
gMVP		0.00026
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs959216315; hg19: chr4-88537495;