4-87658902-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004407.4(DMP1):c.103-318A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 344,318 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0097 (10 hom., cov: 32)
  • Exomes 𝑓: 0.013 (35 hom.)
• Consequence: DMP1 NM_004407.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0260

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-87658902-A-G is Benign according to our data. Variant chr4-87658902-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1194891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00966 (1472/152322) while in subpopulation SAS AF= 0.0201 (97/4820). AF 95% confidence interval is 0.0169. There are 10 homozygotes in gnomad4. There are 674 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMP1	NM_004407.4	c.103-318A>G		intron_variant		ENST00000339673.11
LOC105377323	XR_938960.3	n.649-1493T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMP1	ENST00000339673.11	c.103-318A>G		intron_variant		1	NM_004407.4	P1
	ENST00000506480.5	n.322+14088T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00964 AC: 1468 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0131 AC: 2523 AN: 191996 Hom.: 35 Cov.: 0 AF XY: 0.0137 AC XY: 1412 AN XY: 102858

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0207

Gnomad4 FIN exome AF: 0.00369

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00966 AC: 1472 AN: 152322 Hom.: 10 Cov.: 32 AF XY: 0.00905 AC XY: 674 AN XY: 74476

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00953 Hom.: 0

Bravo AF: 0.00983

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.0
Dann	Benign	0.67

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: rs146295699; hg19: chr4-88580054;