4-87657335-T-C

Position:

• chr4-87657335-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004407.4(DMP1):​c.102+256T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 295,536 control chromosomes in the GnomAD database, including 51,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29489 hom., cov: 31)
  • Exomes 𝑓: 0.54 (21641 hom.)
• Consequence: DMP1 NM_004407.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.490

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]

LOC105377323 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 4-87657335-T-C is Benign according to our data. Variant chr4-87657335-T-C is described in ClinVar as [Benign]. Clinvar id is 1266679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMP1	NM_004407.4	c.102+256T>C		intron_variant		ENST00000339673.11
LOC105377323	XR_938960.3	n.723A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMP1	ENST00000339673.11	c.102+256T>C		intron_variant		1	NM_004407.4	P1
	ENST00000506480.5	n.322+15655A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92094 AN: 151808 Hom.: 29449 Cov.: 31

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.541 AC: 77753 AN: 143612 Hom.: 21641 Cov.: 0 AF XY: 0.543 AC XY: 40721 AN XY: 75046

Gnomad4 AFR exome AF: 0.813

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.616

Gnomad4 NFE exome AF: 0.511

Gnomad4 OTH exome AF: 0.556

GnomAD4 genome AF: 0.607 AC: 92199 AN: 151924 Hom.: 29489 Cov.: 31 AF XY: 0.610 AC XY: 45314 AN XY: 74264

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.549

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.505

Gnomad4 OTH AF: 0.560

Alfa AF: 0.512 Hom.: 21202

Bravo AF: 0.612

Asia WGS AF: 0.684 AC: 2373 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.52

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: rs1545735; hg19: chr4-88578487;