4-87661983-AGC-TGT

Variant names:

• chr4-87661983-AGC-TGT
• NM_004407.4:c.205_207delAGCinsTGT
• DMP1 p.Ser69Cys

Variant summary

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

The NM_004407.4(DMP1):​c.205_207delAGCinsTGT​(p.Ser69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S69G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DMP1 NM_004407.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 0 ACMG points.

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.205_207delAGCinsTGT	p.Ser69Cys	missense	N/A	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.157_159delAGCinsTGT	p.Ser53Cys	missense	N/A	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+11005_366+11007delGCTinsACA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.205_207delAGCinsTGT	p.Ser69Cys	missense	N/A	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.157_159delAGCinsTGT	p.Ser53Cys	missense	N/A	ENSP00000282479.6	Q13316-2
	DMP1	ENST00000682752.1		n.*116_*118delAGCinsTGT		non_coding_transcript_exon	Exon 7 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-88583135;