rs1191357776

Variant names:

• chr4-87657053-G-C
• rs1191357776
• NM_004407.4:c.76G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-87657053-G-C
• chr4-87657053-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004407.4(DMP1):​c.76G>C​(p.Glu26Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,559,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DMP1 NM_004407.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.76G>C	p.Glu26Gln	missense	Exon 3 of 6	NP_004398.1	Q13316-1
	DMP1	NM_001079911.3		c.76G>C	p.Glu26Gln	missense	Exon 3 of 5	NP_001073380.1	Q13316-2
	DMP1-AS1	NR_198971.1		n.366+15937C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.76G>C	p.Glu26Gln	missense	Exon 3 of 6	ENSP00000340935.6	Q13316-1
	DMP1	ENST00000282479.8	TSL:1	c.76G>C	p.Glu26Gln	missense	Exon 3 of 5	ENSP00000282479.6	Q13316-2
	DMP1	ENST00000682752.1		n.76G>C		non_coding_transcript_exon	Exon 3 of 7	ENSP00000507436.1	A0A804HJB8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1407230 Hom.: 0 Cov.: 25 AF XY: 0.00000142 AC XY: 1 AN XY: 703118

African (AFR) AF: 0.00 AC: 0 AN: 32464

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 84744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 9.41e-7 AC: 1 AN: 1062828

Other (OTH) AF: 0.00 AC: 0 AN: 58512

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.0055
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.29
MutPred		0.57		Loss of helix (P = 0.0237)
MVP		0.86
MPC		0.35
ClinPred		0.77	D
GERP RS		4.8
Varity_R		0.12
gMVP		0.13
Mutation Taster		=94/6	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: rs1191357776; hg19: chr4-88578205;