rs36089093

Variant names:

• chr4-87650292-CA-C
• rs36089093
• NM_004407.4:c.-112delA

Your query was ambiguous. Multiple possible variants found:

• chr4-87650292-CA-C
• chr4-87650292-CA-CAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004407.4(DMP1):​c.-112delA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,148 control chromosomes in the GnomAD database, including 2,221 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2221 hom., cov: 29)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: DMP1 NM_004407.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23
• 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 -10 ACMG points.

• BP6: Variant 4-87650292-CA-C is Benign according to our data. Variant chr4-87650292-CA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 369444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.218 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.-112delA		5_prime_UTR	Exon 1 of 6	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.-112delA		5_prime_UTR	Exon 1 of 5	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+22697delT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.-112delA		5_prime_UTR	Exon 1 of 6	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000682752.1		n.-112delA		non_coding_transcript_exon	Exon 1 of 7	ENSP00000507436.1	A0A804HJB8
	DMP1	ENST00000682752.1		n.-112delA		5_prime_UTR	Exon 1 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22963 AN: 152026 Hom.: 2221 Cov.: 29

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.151 AC: 22963 AN: 152144 Hom.: 2221 Cov.: 29 AF XY: 0.149 AC XY: 11083 AN XY: 74402

African (AFR) AF: 0.0392 AC: 1628 AN: 41544

American (AMR) AF: 0.225 AC: 3432 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 772 AN: 3464

East Asian (EAS) AF: 0.148 AC: 768 AN: 5172

South Asian (SAS) AF: 0.0851 AC: 410 AN: 4820

European-Finnish (FIN) AF: 0.129 AC: 1368 AN: 10590

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13948 AN: 67972

Other (OTH) AF: 0.188 AC: 396 AN: 2108

Alfa AF: 0.177 Hom.: 329

Bravo AF: 0.153

Asia WGS AF: 0.104 AC: 365 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypophosphatemic Rickets, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs36089093; hg19: chr4-88571444;