rs79402270

Positions:

chr4-87662253-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000339673.11(DMP1):c.475C>A(p.Gln159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,614,116 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 211 hom. )

Consequence

DMP1
ENST00000339673.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0930

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030641854).

BP6

Variant 4-87662253-C-A is Benign according to our data. Variant chr4-87662253-C-A is described in ClinVar as [Benign]. Clinvar id is 349974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87662253-C-A is described in Lovd as [Likely_pathogenic].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMP1	NM_004407.4 linkuse as main transcript	c.475C>A	p.Gln159Lys	missense_variant	6/6	ENST00000339673.11	NP_004398.1
LOC105377323	XR_938960.3 linkuse as main transcript	n.649-4844G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMP1	ENST00000339673.11 linkuse as main transcript	c.475C>A	p.Gln159Lys	missense_variant	6/6	1	NM_004407.4	ENSP00000340935	P1	Q13316-1
	ENST00000506480.5 linkuse as main transcript	n.322+10737G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00547

AC:

832

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.0494

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.0154

AC:

3864

AN:

251084

Hom.:

138

AF XY:

0.0123

AC XY:

1663

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000863

Gnomad AMR exome

AF:

0.0759

Gnomad ASJ exome

AF:

0.00527

Gnomad EAS exome

AF:

0.0493

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.000648

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.00542

AC:

7930

AN:

1461872

Hom.:

211

Cov.:

AF XY:

0.00499

AC XY:

3632

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0687

Gnomad4 ASJ exome

AF:

0.00551

Gnomad4 EAS exome

AF:

0.0571

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.000581

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00429

GnomAD4 genome

AF:

0.00548

AC:

834

AN:

152244

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

417

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000819

Gnomad4 AMR

AF:

0.0245

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.0495

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00515

Hom.:

Bravo

AF:

0.00896

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.0126

AC:

1525

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2018	This variant is associated with the following publications: (PMID: 29340306, 27820122, 21050253) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypophosphatemic rickets, autosomal recessive, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.077

Sift

Benign

0.058

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.99

D;D

Vest4

0.029

MPC

0.31

ClinPred

0.025

GERP RS

3.4

Varity_R

0.28

gMVP

0.0063

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