DMP1c.273delUncertain significance

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Variant interpretation report

DMP1 c.273del, p.(Ser92ProfsTer141)

NM_004407.4:c.273del NP_004398.1:p.(Ser92ProfsTer141) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About DMP1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 1 Pathogenic
Pipeline record: 7 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): NM_004407.4:c.273del is a frameshift variant in exon 6 (last exon) of DMP1, predicted to result in a premature termination codon at p.(Ser92ProfsTer141). DMP1 loss of function is an established mechanism for autosomal recessive hypophosphatemic rickets type 1 (ARHR1), supported by multiple germline disease-focused publications. Under ClinGen SVI PVS1 recommendations (PMC6185798), the variant is in the last exon and is not predicted to undergo nonsense-mediated decay, but removes over 80% of the protein; downgraded from very strong to strong.
PM2 (supporting): This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF= 4.96e-06, 8/1,614,126 alleles, 0 homozygotes), well below the 0.1% PM2 threshold. Highest subpopulation frequency is European (non-Finnish) at AF= 6.78e-06.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Strong

PVS1 · strong

NM_004407.4:c.273del is a frameshift variant in exon 6 (last exon) of DMP1, predicted to result in a premature termination codon at p.(Ser92ProfsTer141). DMP1 loss of function is an established mechanism for autosomal recessive hypophosphatemic rickets type 1 (ARHR1), supported by multiple germline disease-focused publications. Under ClinGen SVI PVS1 recommendations (PMC6185798), the variant is in the last exon and is not predicted to undergo nonsense-mediated decay, but removes over 80% of the protein; downgraded from very strong to strong.

PM2Supporting

PM2 · supporting

This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF= 4.96e-06, 8/1,614,126 alleles, 0 homozygotes), well below the 0.1% PM2 threshold. Highest subpopulation frequency is European (non-Finnish) at AF= 6.78e-06.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 supporting; combination = 1 strong + 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

8 / 1,614,126 alleles

gnomAD v4.1: 8 / 1,614,126 alleles. Recorded AF 4.95624e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 Pathogenic. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_004407.4:c.273del (p.Ser92ProfsTer141) is a frameshift deletion in exon 6 of DMP1 predicted to remove over 80% of the protein. DMP1 loss of function is an established mechanism for autosomal recessive hypophosphatemic rickets type 1 (ARHR1), satisfying PVS1 at strong strength under ClinGen SVI PVS1 guidelines (PMC6185798); the variant is in the last exon and NMD is not predicted, warranting a one-level downgrade from very strong.

This variant is extremely rare in population databases: absent from gnomAD v2.1 and present at 0.00050% in gnomAD v4.1 (8 of 1,614,126 alleles, no homozygotes), meeting PM2 at supporting level.

SpliceAI predicts no splice-altering impact (max delta = 0.07). REVEL and BayesDel scores are not available for this non-SNV variant. PP3 is not met.

This variant has been reported in ClinVar as Pathogenic by a single clinical laboratory (Labcorp Genetics/Invitae, SCV007399047). The submitter's cited evidence could not be independently confirmed: PMID:19796717 reports a different DMP1 variant (c.485Tdel) and does not mention c.273del; PMID:28492532 is a methodology paper with no variant-specific content. PP5 is not met.

Overall classification: Variant of Uncertain Significance (VUS). One strong criterion (PVS1) and one supporting criterion (PM2) are met. Under generic ACMG/AMP 2015 combination rules, this does not reach the threshold for Likely Pathogenic (which requires PVS1_Strong combined with at least 1 moderate or at least 2 supporting criteria). Additional evidence including variant-specific functional studies, case observations, or cosegregation data would be needed to upgrade this classification.

Met · 2

PVS1 StrongNM_004407.4:c.273del is a frameshift variant in exon 6 (last exon) of DMP1, predicted to result in a premature termination codon at p.(Ser92ProfsTer141). DMP1 loss of function is an established mechanism for autosomal recessive hypophosphatemic rickets type 1 (ARHR1), supported by multiple germline disease-focused publications. Under ClinGen SVI PVS1 recommendations (PMC6185798), the variant is in the last exon and is not predicted to undergo nonsense-mediated decay, but removes over 80% of the protein; downgraded from very strong to strong. Details ▾Hide ▴

Evidence considered

Frameshift variant in DMP1 (MANE Select transcript NM_004407.4) resulting in p.Ser92ProfsTer141
removing >80% of the 514-amino-acid protein
DMP1 LoF mechanism firmly established for autosomal recessive hypophosphatemic rickets type 1 (ARHR1)
Variant in last exon (exon 6)
NMD not predicted per PMC6185798
PVS1_Strong applied per PMC6185798 guidance for NMD-escape truncating variants with substantial protein loss

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF= 4.96e-06, 8/1,614,126 alleles, 0 homozygotes), well below the 0.1% PM2 threshold. Highest subpopulation frequency is European (non-Finnish) at AF= 6.78e-06. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exome)
gnomAD v4.1: 8/1
614
126 alleles (AF=0.00050%)
0 homozygotes
grpmax FAF=2.92e-06
highest subpopulation AF=0.00068% (European non-Finnish)

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observation with confirmed parentage has been reported for this variant. Details ▾Hide ▴

Still missing

No de novo testing data available

PS3 No well-established functional studies demonstrating a damaging effect specific to NM_004407.4:c.273del have been identified. PMID:19796717 reports functional characterization of a different DMP1 variant (c.485Tdel) but does not mention c.273del. Details ▾Hide ▴

Still missing

No variant-specific functional data available

PS4 Insufficient data to demonstrate statistically significant enrichment in affected individuals compared to controls. One ClinVar submission reports this variant as pathogenic, but no case-control study or prevalence data are available. Details ▾Hide ▴

Still missing

No case-control or case-series data for this variant

PM1 This variant does not reside within a known mutational hotspot or critical functional domain as assessed by cancerhotspots.org and domain analysis. Details ▾Hide ▴

Evidence considered

Not located in a statistically significant hotspot

PM6 No assumed de novo observation has been reported for this variant. Details ▾Hide ▴

Still missing

No de novo reports available

PP1 No cosegregation data available for NM_004407.4:c.273del with disease in multiple affected family members. PMID:19796717 describes cosegregation of a different DMP1 variant (c.485Tdel) in an ARHP kindred but does not involve this variant. Details ▾Hide ▴

Still missing

No variant-specific cosegregation data

PP3 No computational evidence supports a deleterious effect for this variant. REVEL and BayesDel scores are not available for frameshift variants. SpliceAI predicts no splice-altering impact (max delta score = 0.07). Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.07 (no predicted splice impact)
REVEL/BayesDel not applicable to non-SNV variants

Sources

spliceai ↗

PP4 No patient-specific phenotype or family history data are available for assessment. PP4 requires the patient's phenotype to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴

Still missing

No patient phenotype data provided

PP5 This variant has been reported as Pathogenic in ClinVar by a single clinical laboratory (Labcorp Genetics/Invitae, SCV007399047, criteria provided, single submitter). PP5 requires a reputable source with accessible evidence; a single submitter without expert panel validation or shared underlying evidence does not meet the PP5 threshold under generic ACMG/AMP. Details ▾Hide ▴

Evidence considered

ClinVar VariationID 4732576: Pathogenic
1 submitter (Labcorp Genetics/Invitae)
criteria provided
single submitter

Still missing

Single submitter without expert panel review
underlying evidence not independently verifiable

Sources

clinvar ↗

BA1 This variant is not present at an allele frequency >1% in any population in gnomAD. Highest AF is 0.00068% in European (non-Finnish), far below the BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 maximum population AF = 0.00068% (European non-Finnish)
well below 1% BA1 threshold

Sources

gnomad_v4 ↗

BS1 This variant is not present at an allele frequency >0.3% in any population in gnomAD. Highest AF is 0.00068% in European (non-Finnish), far below the BS1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 maximum population AF = 0.00068% (European non-Finnish)
well below 0.3% BS1 threshold

Sources

gnomad_v4 ↗

BS2 No healthy adult homozygous individuals have been observed for this variant in population databases (gnomAD homozygote count = 0). For an autosomal recessive disorder such as ARHR1, BS2 requires observation of the variant in a homozygous state in a healthy adult. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 0 homozygotes observed across 1
614
126 alleles

Sources

gnomad_v4 ↗

BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant. Details ▾Hide ▴

Still missing

No benign functional evidence available

BS4 No evidence of non-segregation with disease has been reported for this variant. Details ▾Hide ▴

Still missing

No segregation data available

BP2 No evidence of this variant observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, has been identified. Details ▾Hide ▴

Still missing

No phase data available

BP5 No report of this variant in a case with an alternate molecular basis for disease has been identified. Details ▾Hide ▴

Still missing

No alternate-molecular-basis data available

BP6 ClinVar reports this variant as Pathogenic (1 submitter), not as benign. BP6 applies when a reputable source reports the variant as benign. Details ▾Hide ▴

Evidence considered

ClinVar VariationID 4732576: classified as Pathogenic
not benign
BP6 not applicable

Sources

clinvar ↗

PS5 No expert panel, practice guideline, or other authoritative source has independently reported this variant as pathogenic with accessible evidence. Details ▾Hide ▴

Still missing

No expert panel or practice guideline classification available

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to variants producing the same amino acid change as a known pathogenic variant via a different nucleotide change; not applicable to frameshift variants. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift deletion; protein-truncating effect is already captured by PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense variants at residues where a different pathogenic missense change has been observed. This variant is a frameshift deletion; PM5 missense comparator semantics cannot be applied. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with low rates of benign missense variation and where missense variants are a common disease mechanism. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is a frameshift (truncating), not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This variant is a frameshift deletion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/AIn silico pathogenicity predictors (REVEL, BayesDel) are not validated for frameshift variant assessment. SpliceAI alone (delta = 0.07) is insufficient to satisfy the multiple-lines-of-evidence requirement for BP4. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: DMP1
Transcript: NM_004407.4
Coding (HGVS c.): NM_004407.4:c.273del
Protein (HGVS p.): NP_004398.1:p.(Ser92ProfsTer141)
GRCh38: chr4:87662050 TC>T
GRCh37: chr4:88583202 TC>T
ClinVar: 4732576

Gene diagram

Every interpreted variant in DMP1, mapped onto the exon structure of NM_004407.4. Select a row to find it on the plot.

DMP1NM_004407.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in DMP1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 8 / 1,614,126 alleles AF 4.96e-06 · 0 homozygotes · FAF 2.92e-06

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5e-06 · 8 / 1,614,126 alleles · 0 hom · FAF 2.9e-06

European (non-Finnish)8 / 1,180,020

6.8e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.95624e-06; MAF= 0.00050%, 8/1614126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.77955e-06; MAF= 0.00068%, 8/1180020 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -88 bp

0.030

SpliceAI acceptor gainat -14 bp

0.070

SpliceAI donor lossat +287 bp

0.000

SpliceAI donor gainat +269 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.07 (no predicted splice impact)
REVEL/BayesDel not applicable to non-SNV variants

Sources

spliceai ↗

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

Turan S et al. · 2010

Turan et al. (2010) describe a consanguineous kindred with autosomal recessive hypophosphatemia carrying a novel homozygous DMP1 mutation c.485Tdel (p.Glu163ArgfsX53) in exon 6. The paper also discusses previously reported DMP1 mutations (c.362delC, c.del1484-1490, c.1A>G). NM_004407.4:c.273del was not identified in this paper.
Does not name this variant
PMID 19796717 ↗
Quoted passage
a novel homozygous mutation in exon 6 (c.485Tdel) that resulted in a frame-shift replacing the 335 conserved amino acids within the carboxy-terminal portion of DMP-1
Results section; mutation identified as c.485Tdel in exon 6, not c.273del

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 8 / 1,614,126 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.070 Open source ↗

ClinVar 1 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 4732576)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.