4-87657057-C-T

Position:

chr4-87657057-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_004407.4(DMP1):c.80C>T(p.Ser27Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,557,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

DMP1
NM_004407.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.860

Variant links:

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 links:

ENSG00000249001 (HGNC:58144):

ENSG00000249001 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10494575).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000158 (24/152140) while in subpopulation AFR AF= 0.000579 (24/41424). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMP1	NM_004407.4 link	c.80C>T	p.Ser27Phe	missense_variant	3/6	ENST00000339673.11	NP_004398.1	Q13316-1
DMP1	NM_001079911.3 link	c.80C>T	p.Ser27Phe	missense_variant	3/5		NP_001073380.1	Q13316-2
DMP1	XM_011531705.3 link	c.167C>T	p.Ser56Phe	missense_variant	3/6		XP_011530007.1
DMP1	XM_011531706.3 link	c.167C>T	p.Ser56Phe	missense_variant	3/5		XP_011530008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMP1	ENST00000339673.11 link	c.80C>T	p.Ser27Phe	missense_variant	3/6	1	NM_004407.4	ENSP00000340935.6		Q13316-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

250126

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.000890

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1405236

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

702250

show subpopulations

Gnomad4 AFR exome

AF:

0.000770

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:

0.00

Gnomad4 OTH exome

AF:

0.0000342

GnomAD4 genome

AF:

0.000158

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000579

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000492

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000742

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.80C>T (p.S27F) alteration is located in exon 3 (coding exon 2) of the DMP1 gene. This alteration results from a C to T substitution at nucleotide position 80, causing the serine (S) at amino acid position 27 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.088

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.97

D;D

Vest4

0.43

MVP

0.81

MPC

0.21

ClinPred

0.14

GERP RS

4.8

Varity_R

0.25

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over