chr4-87656267-T-C

Variant names:

• chr4-87656267-T-C
• rs2627702
• NM_004407.4:c.-21-205T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004407.4(DMP1):​c.-21-205T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 152,078 control chromosomes in the GnomAD database, including 29,525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.61 (29525 hom., cov: 33)
• Consequence: DMP1 NM_004407.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.87
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-87656267-T-C is Benign according to our data. Variant chr4-87656267-T-C is described in ClinVar as Benign. ClinVar VariationId is 1234211.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

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.-21-205T>C		intron	N/A	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.-21-205T>C		intron	N/A	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+16723A>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.-21-205T>C		intron	N/A	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.-21-205T>C		intron	N/A	ENSP00000282479.6	Q13316-2
	DMP1-AS1	ENST00000506480.5	TSL:3	n.322+16723A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92201 AN: 151960 Hom.: 29484 Cov.: 33

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.607 AC: 92308 AN: 152078 Hom.: 29525 Cov.: 33 AF XY: 0.610 AC XY: 45351 AN XY: 74336

African (AFR) AF: 0.813 AC: 33736 AN: 41518

American (AMR) AF: 0.550 AC: 8381 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1062 AN: 3468

East Asian (EAS) AF: 0.683 AC: 3544 AN: 5186

South Asian (SAS) AF: 0.594 AC: 2862 AN: 4822

European-Finnish (FIN) AF: 0.625 AC: 6609 AN: 10566

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.505 AC: 34334 AN: 67954

Other (OTH) AF: 0.561 AC: 1183 AN: 2110

Alfa AF: 0.567 Hom.: 3398

Bravo AF: 0.612

Asia WGS AF: 0.684 AC: 2375 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.47
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2627702; hg19: chr4-88577419;