4-87661983-A-T

Variant names:

• chr4-87661983-A-T
• rs10019009
• NM_004407.4:c.205A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004407.4(DMP1):​c.205A>T​(p.Ser69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,724 control chromosomes in the GnomAD database, including 63,234 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S69G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (6266 hom., cov: 31)
  • Exomes 𝑓: 0.27 (56968 hom.)
• Consequence: DMP1 NM_004407.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.31
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004264474).
• BP6: Variant 4-87661983-A-T is Benign according to our data. Variant chr4-87661983-A-T is described in ClinVar as Benign. ClinVar VariationId is 349970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	NM_004407.4	MANE Select	c.205A>T	p.Ser69Cys	missense	Exon 6 of 6	NP_004398.1
	DMP1	NM_001079911.3		c.157A>T	p.Ser53Cys	missense	Exon 5 of 5	NP_001073380.1
	DMP1-AS1	NR_198971.1		n.366+11007T>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMP1	ENST00000339673.11	TSL:1 MANE Select	c.205A>T	p.Ser69Cys	missense	Exon 6 of 6	ENSP00000340935.6
	DMP1	ENST00000282479.8	TSL:1	c.157A>T	p.Ser53Cys	missense	Exon 5 of 5	ENSP00000282479.6
	DMP1	ENST00000682752.1		n.*116A>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000507436.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42642 AN: 151920 Hom.: 6262 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.287 AC: 72253 AN: 251340 AF XY: 0.276

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.423

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.275 AC: 401872 AN: 1461686 Hom.: 56968 Cov.: 37 AF XY: 0.270 AC XY: 196653 AN XY: 727152

African (AFR) AF: 0.284 AC: 9518 AN: 33478

American (AMR) AF: 0.382 AC: 17073 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2743 AN: 26136

East Asian (EAS) AF: 0.407 AC: 16145 AN: 39700

South Asian (SAS) AF: 0.210 AC: 18082 AN: 86250

European-Finnish (FIN) AF: 0.337 AC: 17996 AN: 53420

Middle Eastern (MID) AF: 0.121 AC: 695 AN: 5766

European-Non Finnish (NFE) AF: 0.273 AC: 303097 AN: 1111830

Other (OTH) AF: 0.274 AC: 16523 AN: 60388

GnomAD4 genome AF: 0.281 AC: 42654 AN: 152038 Hom.: 6266 Cov.: 31 AF XY: 0.283 AC XY: 21038 AN XY: 74318

African (AFR) AF: 0.289 AC: 11986 AN: 41470

American (AMR) AF: 0.305 AC: 4659 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3466

East Asian (EAS) AF: 0.424 AC: 2172 AN: 5120

South Asian (SAS) AF: 0.219 AC: 1057 AN: 4822

European-Finnish (FIN) AF: 0.354 AC: 3749 AN: 10580

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17830 AN: 67970

Other (OTH) AF: 0.255 AC: 539 AN: 2112

Alfa AF: 0.244 Hom.: 3725

Bravo AF: 0.284

TwinsUK AF: 0.277 AC: 1028

ALSPAC AF: 0.270 AC: 1042

ESP6500AA AF: 0.296 AC: 1302

ESP6500EA AF: 0.266 AC: 2289

ExAC AF: 0.281 AC: 34167

Asia WGS AF: 0.328 AC: 1138 AN: 3478

EpiCase AF: 0.244

EpiControl AF: 0.236

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypophosphatemic rickets, autosomal recessive, 1 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.091
MPC		0.34
ClinPred		0.055	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.12
Mutation Taster		=97/3	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: rs10019009; hg19: chr4-88583135; COSMIC: COSV56818589; COSMIC: COSV56818589;