chr4-87657029-T-G

Position:

chr4-87657029-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_004407.4(DMP1):c.55-3T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,534,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

DMP1
NM_004407.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9912

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.130

Variant links:

Genes affected

DMP1 (HGNC:2932): (dentin matrix acidic phosphoprotein 1) Dentin matrix acidic phosphoprotein is an extracellular matrix protein and a member of the small integrin binding ligand N-linked glycoprotein family. This protein, which is critical for proper mineralization of bone and dentin, is present in diverse cells of bone and tooth tissues. The protein contains a large number of acidic domains, multiple phosphorylation sites, a functional arg-gly-asp cell attachment sequence, and a DNA binding domain. In undifferentiated osteoblasts it is primarily a nuclear protein that regulates the expression of osteoblast-specific genes. During osteoblast maturation the protein becomes phosphorylated and is exported to the extracellular matrix, where it orchestrates mineralized matrix formation. Mutations in the gene are known to cause autosomal recessive hypophosphatemia, a disease that manifests as rickets and osteomalacia. The gene structure is conserved in mammals. Two transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

DMP1 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000195 (269/1382456) while in subpopulation MID AF= 0.00985 (55/5586). AF 95% confidence interval is 0.00777. There are 0 homozygotes in gnomad4_exome. There are 135 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DMP1	NM_004407.4 linkuse as main transcript	c.55-3T>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000339673.11
DMP1	NM_001079911.3 linkuse as main transcript	c.55-3T>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DMP1	XM_011531705.3 linkuse as main transcript	c.142-3T>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DMP1	XM_011531706.3 linkuse as main transcript	c.142-3T>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMP1	ENST00000339673.11 linkuse as main transcript	c.55-3T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004407.4	P1	Q13316-1
	ENST00000506480.5 linkuse as main transcript	n.322+15961A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000244

AC:

AN:

250474

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000983

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000362

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000195

AC:

269

AN:

1382456

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

135

AN XY:

691984

show subpopulations

Gnomad4 AFR exome

AF:

0.0000938

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.000664

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000593

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000144

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000190

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000475

Hom.:

Bravo

AF:

0.000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	This sequence change falls in intron 2 of the DMP1 gene. It does not directly change the encoded amino acid sequence of the DMP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs181490843, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DMP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 288212). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2018	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypophosphatemic rickets, autosomal recessive, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 11

DS_AL_spliceai

0.38

Position offset: 3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over