Genetic Variant DMP1:p.Lys2Glu (chr4-87656496-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004407.4(DMP1):c.4A>G(p.Lys2Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DMP1
NM_004407.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypophosphatemic rickets, autosomal recessive, 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive hypophosphatemic rickets
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DMP1 links:

DMP1-AS1 (HGNC:58144):

DMP1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004407.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMP1	NM_004407.4	MANE Select	c.4A>G	p.Lys2Glu	missense	Exon 2 of 6	NP_004398.1	Q13316-1
DMP1	NM_001079911.3		c.4A>G	p.Lys2Glu	missense	Exon 2 of 5	NP_001073380.1	Q13316-2
DMP1-AS1	NR_198971.1		n.366+16494T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMP1	ENST00000339673.11	TSL:1 MANE Select	c.4A>G	p.Lys2Glu	missense	Exon 2 of 6	ENSP00000340935.6	Q13316-1
DMP1	ENST00000282479.8	TSL:1	c.4A>G	p.Lys2Glu	missense	Exon 2 of 5	ENSP00000282479.6	Q13316-2
DMP1	ENST00000682752.1		n.4A>G		non_coding_transcript_exon	Exon 2 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.0039

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.49

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.3

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.42

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.94

Vest4

0.49

MutPred

0.67

Loss of ubiquitination at K2 (P = 0.0192)

MVP

0.90

MPC

0.27

ClinPred

0.95

GERP RS

5.6

Varity_R

0.41

gMVP

0.24

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over