rs2615480

Variant names:

• chr4-87656421-A-G
• rs2615480
• NM_004407.4:c.-21-51A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-87656421-A-G
• chr4-87656421-A-C
• chr4-87656421-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004407.4(DMP1):​c.-21-51A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 1,046,094 control chromosomes in the GnomAD database, including 291,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46936 hom., cov: 32)
  • Exomes 𝑓: 0.74 (244445 hom.)
• Consequence: DMP1 NM_004407.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.545
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-87656421-A-G is Benign according to our data. Variant chr4-87656421-A-G is described in ClinVar as Benign. ClinVar VariationId is 1179610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.881 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.-21-51A>G		intron	N/A	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.-21-51A>G		intron	N/A	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+16569T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.-21-51A>G		intron	N/A	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.-21-51A>G		intron	N/A	ENSP00000282479.6	Q13316-2
	DMP1-AS1	ENST00000506480.5	TSL:3	n.322+16569T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118688 AN: 152052 Hom.: 46880 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.804

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.778

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.719

Gnomad OTH AF: 0.766

GnomAD4 exome AF: 0.736 AC: 658224 AN: 893924 Hom.: 244445 AF XY: 0.733 AC XY: 343432 AN XY: 468558

African (AFR) AF: 0.890 AC: 19806 AN: 22246

American (AMR) AF: 0.858 AC: 37663 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 12542 AN: 22598

East Asian (EAS) AF: 0.861 AC: 31919 AN: 37064

South Asian (SAS) AF: 0.719 AC: 53700 AN: 74688

European-Finnish (FIN) AF: 0.775 AC: 40565 AN: 52362

Middle Eastern (MID) AF: 0.783 AC: 3653 AN: 4664

European-Non Finnish (NFE) AF: 0.719 AC: 427287 AN: 594608

Other (OTH) AF: 0.744 AC: 31089 AN: 41776

GnomAD4 genome AF: 0.781 AC: 118802 AN: 152170 Hom.: 46936 Cov.: 32 AF XY: 0.782 AC XY: 58197 AN XY: 74386

African (AFR) AF: 0.888 AC: 36906 AN: 41552

American (AMR) AF: 0.804 AC: 12290 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1910 AN: 3466

East Asian (EAS) AF: 0.891 AC: 4612 AN: 5176

South Asian (SAS) AF: 0.722 AC: 3473 AN: 4808

European-Finnish (FIN) AF: 0.778 AC: 8245 AN: 10598

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.719 AC: 48900 AN: 67968

Other (OTH) AF: 0.768 AC: 1626 AN: 2116

Alfa AF: 0.755 Hom.: 5736

Bravo AF: 0.790

Asia WGS AF: 0.831 AC: 2892 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.79
DANN	Benign	0.69
PhyloP100		-0.55
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: rs2615480; hg19: chr4-88577573; COSMIC: COSV56820266; COSMIC: COSV56820266;