rs145237146

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004407.4(DMP1):c.815G>A(p.Arg272His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 3 hom. )

Consequence

DMP1
NM_004407.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.0650

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005351305).

BP6

Variant 4-87662593-G-A is Benign according to our data. Variant chr4-87662593-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 349978.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00196 (299/152280) while in subpopulation AMR AF= 0.00778 (119/15302). AF 95% confidence interval is 0.00664. There are 2 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMP1	NM_004407.4 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	6/6	ENST00000339673.11
LOC105377323	XR_938960.3 linkuse as main transcript	n.649-5184C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMP1	ENST00000339673.11 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	6/6	1	NM_004407.4	P1	Q13316-1
	ENST00000506480.5 linkuse as main transcript	n.322+10397C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00197

AC:

299

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00194

AC:

485

AN:

250358

Hom.:

AF XY:

0.00203

AC XY:

275

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.00403

Gnomad ASJ exome

AF:

0.00140

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00192

AC:

2813

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

1382

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00450

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00211

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152280

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00778

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00213

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00181

AC:

220

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00414

EpiControl

AF:

0.00445

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DMP1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DMP1 p.Arg272His variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs145237146) and ClinVar (classified as uncertain significance by Illumina, EGL Genetic Diagnostics and Fulgent Genetics, and as benign by Invitae). The variant was identified in control databases in 531 of 281746 chromosomes (1 homozygous) at a frequency of 0.001885 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 145 of 35372 chromosomes (freq: 0.004099), Other in 21 of 7198 chromosomes (freq: 0.002917), European (non-Finnish) in 330 of 128426 chromosomes (freq: 0.00257), Ashkenazi Jewish in 14 of 10324 chromosomes (freq: 0.001356), African in 8 of 24814 chromosomes (freq: 0.000322), South Asian in 9 of 30580 chromosomes (freq: 0.000294), European (Finnish) in 3 of 25114 chromosomes (freq: 0.00012), and East Asian in 1 of 19918 chromosomes (freq: 0.00005). The p.Arg272 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypophosphatemic rickets, autosomal recessive, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

DMP1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.5

DANN

Benign

0.86

DEOGEN2

Benign

0.078

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.18

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.025

Sift

Benign

0.16

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.10

B;B

Vest4

0.047

MVP

0.45

MPC

0.069

ClinPred

0.0080

GERP RS

1.0

Varity_R

0.051

gMVP

0.080

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

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