chr4-87662593-G-A

Variant names:

• chr4-87662593-G-A
• rs145237146
• NM_004407.4:c.815G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004407.4(DMP1):​c.815G>A​(p.Arg272His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: DMP1 NM_004407.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.0650
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005351305).
• BP6: Variant 4-87662593-G-A is Benign according to our data. Variant chr4-87662593-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 349978.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00196 (299/152280) while in subpopulation AMR AF = 0.00778 (119/15302). AF 95% confidence interval is 0.00664. There are 2 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.815G>A	p.Arg272His	missense	Exon 6 of 6	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.767G>A	p.Arg256His	missense	Exon 5 of 5	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+10397C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.815G>A	p.Arg272His	missense	Exon 6 of 6	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.767G>A	p.Arg256His	missense	Exon 5 of 5	ENSP00000282479.6	Q13316-2
	DMP1	ENST00000682752.1		n.*726G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 299 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00194 AC: 485 AN: 250358 AF XY: 0.00203

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00192 AC: 2813 AN: 1461766 Hom.: 3 Cov.: 33 AF XY: 0.00190 AC XY: 1382 AN XY: 727168

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.00450 AC: 201 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86238

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53372

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.00211 AC: 2342 AN: 1111964

Other (OTH) AF: 0.00232 AC: 140 AN: 60394

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74476

African (AFR) AF: 0.000553 AC: 23 AN: 41554

American (AMR) AF: 0.00778 AC: 119 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68018

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00233 Hom.: 3

Bravo AF: 0.00238

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	2	1	Hypophosphatemic rickets, autosomal recessive, 1 (3)
-	-	1	DMP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.5
DANN	Benign	0.86
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.065
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.025
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.10	B
Vest4		0.047
MVP		0.45
MPC		0.069
ClinPred		0.0080	T
GERP RS		1.0
Varity_R		0.051
gMVP		0.080
Mutation Taster		=100/0	polymorphism

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: rs145237146; hg19: chr4-88583745; COSMIC: COSV56819010; COSMIC: COSV56819010;