4-87656493-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PVS1_SupportingPM2BS1_Supporting

The NM_004407.4(DMP1):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000344 in 1,453,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DMP1
NM_004407.4 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3B:1

Conservation

PhyloP100: 3.81

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:

ENSG00000249001 (HGNC:58144):

ENSG00000249001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 21 CDS bases. Genomic position: 87656513. Lost 0.014 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000344 (5/1453326) while in subpopulation MID AF= 0.000521 (3/5756). AF 95% confidence interval is 0.000142. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 29. 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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMP1	NM_004407.4 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 6	ENST00000339673.11	NP_004398.1	Q13316-1
DMP1	NM_001079911.3 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 5		NP_001073380.1	Q13316-2
DMP1	XM_011531705.3 link	c.88A>G	p.Met30Val	missense_variant	Exon 2 of 6		XP_011530007.1
DMP1	XM_011531706.3 link	c.88A>G	p.Met30Val	missense_variant	Exon 2 of 5		XP_011530008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMP1	ENST00000339673.11 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 6	1	NM_004407.4	ENSP00000340935.6		Q13316-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251412

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1453326

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723776

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000422

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 1

Pathogenic:2

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypophosphatemic rickets (MIM#241520). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the initiation codon is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0703 - Other start loss variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.2T>A(p.Met1Lys) has been reported once as pathogenic (ClinVar) and c.1A>T(p.Met1Leu) has been reported once in a compound heterozygous individual with autosomal recessive hypophosphatemic rickets (PMID: 36334264). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as pathogenic in ClinVar. It has also been reported in nine individuals with hypophosphatemic rickets from five unrelated families in the literature (PMIDs: 17033625, 17033621, 25180662, 23038738). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large family (PMID: 17033625). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1

Nov 06, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease (PMID: 17033621); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25180662, 17033625, 18094488, 19007919, 17033621, 25044680) -

not specified

Benign:1

Jan 12, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

T;.

Eigen

Benign

0.076

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.69

PROVEAN

Benign

-0.42

N;N

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.75

P;P

Vest4

0.68

MutPred

0.88

Gain of methylation at K2 (P = 0.0231);Gain of methylation at K2 (P = 0.0231);

MVP

0.77

ClinPred

0.99

GERP RS

4.4

Varity_R

0.81

gMVP

0.25

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