chr4-87656493-A-G

Position:

• chr4-87656493-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The ENST00000339673.11(DMP1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000344 in 1,453,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DMP1 ENST00000339673.11 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 B:1
• Conservation: PhyloP100: 3.81

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000339673.11 (DMP1) was described as [Pathogenic] in ClinVar as 1339444
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMP1	NM_004407.4	c.1A>G	p.Met1?	start_lost	2/6	ENST00000339673.11	NP_004398.1
DMP1	NM_001079911.3	c.1A>G	p.Met1?	start_lost	2/5		NP_001073380.1
DMP1	XM_011531705.3	c.88A>G	p.Met30Val	missense_variant	2/6		XP_011530007.1
DMP1	XM_011531706.3	c.88A>G	p.Met30Val	missense_variant	2/5		XP_011530008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMP1	ENST00000339673.11	c.1A>G	p.Met1?	start_lost	2/6	1	NM_004407.4	ENSP00000340935.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251412 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1453326 Hom.: 0 Cov.: 29 AF XY: 0.00000553 AC XY: 4 AN XY: 723776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000422 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypophosphatemic rickets (MIM#241520). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the initiation codon is present in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0703 - Other start loss variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. c.2T>A(p.Met1Lys) has been reported once as pathogenic (ClinVar) and c.1A>T(p.Met1Leu) has been reported once in a compound heterozygous individual with autosomal recessive hypophosphatemic rickets (PMID: 36334264). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as pathogenic in ClinVar. It has also been reported in nine individuals with hypophosphatemic rickets from five unrelated families in the literature (PMIDs: 17033625, 17033621, 25180662, 23038738). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large family (PMID: 17033625). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2024

Initiation codon variant in a gene for which loss of function is a known mechanism of disease (PMID: 17033621); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25180662, 17033625, 18094488, 19007919, 17033621, 25044680) -

not specified Benign:1

Benign, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T;.
Eigen	Benign	0.076
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	0.43	A;A
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.75	P;P
Vest4		0.68
MutPred		0.88		Gain of methylation at K2 (P = 0.0231);Gain of methylation at K2 (P = 0.0231);
MVP		0.77
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.81
gMVP		0.25

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: rs104893834; hg19: chr4-88577645;