chr4-87662593-G-C

Variant names:

• chr4-87662593-G-C
• rs145237146
• NM_004407.4:c.815G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004407.4(DMP1):​c.815G>C​(p.Arg272Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DMP1 NM_004407.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650
• Publications: 0 publications found

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-AS1 (HGNC:58144):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.264197).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	NM_004407.4	MANE Select	c.815G>C	p.Arg272Pro	missense	Exon 6 of 6	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.767G>C	p.Arg256Pro	missense	Exon 5 of 5	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+10397C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.815G>C	p.Arg272Pro	missense	Exon 6 of 6	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.767G>C	p.Arg256Pro	missense	Exon 5 of 5	ENSP00000282479.6	Q13316-2
	DMP1	ENST00000682752.1		n.*726G>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461766 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	8.4
DANN	Benign	0.93
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.065
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.22	T
Polyphen		0.54	P
Vest4		0.38
MutPred		0.35		Loss of MoRF binding (P = 0.0019)
MVP		0.70
MPC		0.39
ClinPred		0.95	D
GERP RS		1.0
Varity_R		0.47
gMVP		0.13
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs145237146; hg19: chr4-88583745;