rs2615498

Variant names:

• chr4-87662996-C-T
• rs2615498
• NM_004407.4:c.1218C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004407.4(DMP1):​c.1218C>T​(p.Ser406Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,613,888 control chromosomes in the GnomAD database, including 33,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2259 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30786 hom.)
• Consequence: DMP1 NM_004407.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.25
• Publications: 15 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), G2P, Ambry Genetics
• autosomal recessive hypophosphatemic rickets

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DMP1-AS1 (HGNC:58144):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 4-87662996-C-T is Benign according to our data. Variant chr4-87662996-C-T is described in ClinVar as Benign. ClinVar VariationId is 349982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.252 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.1218C>T	p.Ser406Ser	synonymous	Exon 6 of 6	NP_004398.1
	DMP1	NM_001079911.3		c.1170C>T	p.Ser390Ser	synonymous	Exon 5 of 5	NP_001073380.1
	DMP1-AS1	NR_198971.1		n.366+9994G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.1218C>T	p.Ser406Ser	synonymous	Exon 6 of 6	ENSP00000340935.6
	DMP1	ENST00000282479.8	TSL:1	c.1170C>T	p.Ser390Ser	synonymous	Exon 5 of 5	ENSP00000282479.6
	DMP1	ENST00000682752.1		n.*1129C>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000507436.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24171 AN: 151990 Hom.: 2258 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.189 AC: 47402 AN: 251038 AF XY: 0.198

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.232

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.202 AC: 294738 AN: 1461780 Hom.: 30786 Cov.: 36 AF XY: 0.205 AC XY: 148863 AN XY: 727198

African (AFR) AF: 0.0585 AC: 1960 AN: 33478

American (AMR) AF: 0.115 AC: 5153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3393 AN: 26136

East Asian (EAS) AF: 0.234 AC: 9299 AN: 39700

South Asian (SAS) AF: 0.278 AC: 24003 AN: 86254

European-Finnish (FIN) AF: 0.211 AC: 11263 AN: 53408

Middle Eastern (MID) AF: 0.223 AC: 1288 AN: 5768

European-Non Finnish (NFE) AF: 0.204 AC: 226485 AN: 1111918

Other (OTH) AF: 0.197 AC: 11894 AN: 60394

GnomAD4 genome AF: 0.159 AC: 24183 AN: 152108 Hom.: 2259 Cov.: 32 AF XY: 0.161 AC XY: 11954 AN XY: 74346

African (AFR) AF: 0.0653 AC: 2714 AN: 41548

American (AMR) AF: 0.152 AC: 2317 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1235 AN: 5144

South Asian (SAS) AF: 0.264 AC: 1276 AN: 4826

European-Finnish (FIN) AF: 0.204 AC: 2156 AN: 10558

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13538 AN: 67966

Other (OTH) AF: 0.170 AC: 359 AN: 2114

Alfa AF: 0.177 Hom.: 1383

Bravo AF: 0.148

Asia WGS AF: 0.278 AC: 965 AN: 3478

EpiCase AF: 0.199

EpiControl AF: 0.197

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hypophosphatemic rickets, autosomal recessive, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.27
DANN	Benign	0.54
PhyloP100		-1.3
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: rs2615498; hg19: chr4-88584148; COSMIC: COSV56818887; COSMIC: COSV56818887;