NM_014208.3:c.51+141T>C

Variant names:

• chr4-87611100-T-C
• rs72868621
• NM_014208.3:c.51+141T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014208.3(DSPP):​c.51+141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 863,322 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (24 hom., cov: 31)
  • Exomes 𝑓: 0.0026 (18 hom.)
• Consequence: DSPP NM_014208.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.257
• 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, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• dentinogenesis imperfecta

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• 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

DMP1-AS1 (HGNC:58144):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-87611100-T-C is Benign according to our data. Variant chr4-87611100-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1197925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00908 (1379/151872) while in subpopulation AFR AF = 0.0275 (1137/41414). AF 95% confidence interval is 0.0261. There are 24 homozygotes in GnomAd4. There are 648 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1379 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	NM_014208.3	MANE Select	c.51+141T>C		intron	N/A	NP_055023.2	Q9NZW4
	DMP1-AS1	NR_198971.1		n.367-42567A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSPP	ENST00000651931.1	MANE Select	c.51+141T>C		intron	N/A	ENSP00000498766.1	Q9NZW4
	DMP1-AS1	ENST00000506480.5	TSL:3	n.323-42567A>G		intron	N/A
	DMP1-AS1	ENST00000829286.1		n.357-42567A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1376 AN: 151754 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00513

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00261 AC: 1854 AN: 711450 Hom.: 18 AF XY: 0.00270 AC XY: 1010 AN XY: 374672

African (AFR) AF: 0.0282 AC: 492 AN: 17466

American (AMR) AF: 0.00308 AC: 99 AN: 32142

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 69 AN: 19812

East Asian (EAS) AF: 0.0000299 AC: 1 AN: 33486

South Asian (SAS) AF: 0.00503 AC: 318 AN: 63178

European-Finnish (FIN) AF: 0.000532 AC: 25 AN: 46960

Middle Eastern (MID) AF: 0.0210 AC: 66 AN: 3140

European-Non Finnish (NFE) AF: 0.00133 AC: 613 AN: 460248

Other (OTH) AF: 0.00488 AC: 171 AN: 35018

GnomAD4 genome AF: 0.00908 AC: 1379 AN: 151872 Hom.: 24 Cov.: 31 AF XY: 0.00873 AC XY: 648 AN XY: 74252

African (AFR) AF: 0.0275 AC: 1137 AN: 41414

American (AMR) AF: 0.00512 AC: 78 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4808

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10570

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00147 AC: 100 AN: 67920

Other (OTH) AF: 0.0119 AC: 25 AN: 2100

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0109

Asia WGS AF: 0.00318 AC: 12 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.32
DANN	Benign	0.43
PhyloP100		-0.26
Mutation Taster		=100/0	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: rs72868621; hg19: chr4-88532252;