NM_004407.4:c.273del

DMP1 · NP_004398.1:p.(Ser92ProfsTer141) · NM_004407.4

GRCh37: chr4:88583202 TC>T · GRCh38: chr4:87662050 TC>T

Gene: DMP1 Transcript: NM_004407.4

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

DMP1

Transcript

NM_004407.4

Protein

NP_004398.1:p.(Ser92ProfsTer141)

gnomAD AF

4.956242573380269e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to variants producing the same amino acid change as a known pathogenic variant via a different nucleotide change; not applicable to frameshift variants.
PS2	Not met	No de novo observation with confirmed parentage has been reported for this variant.
PS3	Not met	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.
PS4	Not met	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.
PS5	Not met	No expert panel, practice guideline, or other authoritative source has independently reported this variant as pathogenic with accessible evidence.
PM1	Not met	This variant does not reside within a known mutational hotspot or critical functional domain as assessed by cancerhotspots.org and domain analysis.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped per adjudication instructions.
PM4	N/A	PM4 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.
PM5	N/A	PM5 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.
PM6	Not met	No assumed de novo observation has been reported for this variant.
PP1	Not met	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.
PP2	N/A	PP2 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.
PP3	Not met	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).	spliceai
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant.
BS4	Not met	No evidence of non-segregation with disease has been reported for this variant.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is a frameshift (truncating), not a missense variant.
BP2	Not met	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This variant is a frameshift deletion, not an in-frame variant.
BP4	N/A	In 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.
BP5	Not met	No report of this variant in a case with an alternate molecular basis for disease has been identified.
BP6	Not met	ClinVar reports this variant as Pathogenic (1 submitter), not as benign. BP6 applies when a reputable source reports the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.