rs121912987

Positions:

• chr4-87612105-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_014208.3(DSPP):​c.52G>T​(p.Val18Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V18A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSPP NM_014208.3 missense, splice_region
• Scores: Splicing: ADA: 0.2032
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 0.925

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-87612106-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1320199.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, DSPP
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 4-87612105-G-T is Pathogenic according to our data. Variant chr4-87612105-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16856.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-87612105-G-T is described in Lovd as [Pathogenic]. Variant chr4-87612105-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSPP	NM_014208.3	c.52G>T	p.Val18Phe	missense_variant, splice_region_variant	3/5	ENST00000651931.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSPP	ENST00000651931.1	c.52G>T	p.Val18Phe	missense_variant, splice_region_variant	3/5		NM_014208.3	P1
	ENST00000506480.5	n.323-43572C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461492 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Deafness, autosomal dominant nonsyndromic sensorineural 39, with dentinogenesis imperfecta 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Dentinogenesis imperfecta type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Dentinogenesis imperfecta type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.0077
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.57	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.82	A;A
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.62
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.71		Loss of glycosylation at S21 (P = 0.0291);
MVP		0.90
ClinPred		0.66	D
GERP RS		3.1
Varity_R		0.30
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.43		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912987; hg19: chr4-88533257;