rs2615497

chr4-87663008-G-Achr4-87663008-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004407.4(DMP1):c.1230G>A(p.Glu410=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,613,756 control chromosomes in the GnomAD database, including 50,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6500 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43944 hom.)
• Consequence: DMP1 NM_004407.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 4-87663008-G-A is Benign according to our data. Variant chr4-87663008-G-A is described in ClinVar as [Benign]. Clinvar id is 349983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-87663008-G-A is described in Lovd as [Benign]. Variant chr4-87663008-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMP1	NM_004407.4	c.1230G>A	p.Glu410=	synonymous_variant	6/6	ENST00000339673.11
LOC105377323	XR_938960.3	n.649-5599C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMP1	ENST00000339673.11	c.1230G>A	p.Glu410=	synonymous_variant	6/6	1	NM_004407.4	P1
	ENST00000506480.5	n.322+9982C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42495 AN: 151874 Hom.: 6480 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.266

GnomAD3 exomes AF: 0.250 AC: 62591 AN: 250854 Hom.: 8423 AF XY: 0.255 AC XY: 34626 AN XY: 135646

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.251

Gnomad SAS exome AF: 0.351

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.239

GnomAD4 exome AF: 0.241 AC: 352055 AN: 1461764 Hom.: 43944 Cov.: 37 AF XY: 0.245 AC XY: 177868 AN XY: 727186

Gnomad4 AFR exome AF: 0.412

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.187

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.349

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.253

GnomAD4 genome AF: 0.280 AC: 42557 AN: 151992 Hom.: 6500 Cov.: 32 AF XY: 0.282 AC XY: 20981 AN XY: 74296

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.268

Alfa AF: 0.227 Hom.: 2242

Bravo AF: 0.278

Asia WGS AF: 0.328 AC: 1139 AN: 3478

EpiCase AF: 0.235

EpiControl AF: 0.235

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypophosphatemic rickets, autosomal recessive, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.1
Dann	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs2615497; hg19: chr4-88584160; COSMIC: COSV56818512; COSMIC: COSV56818512;