Variant classification summary

NM_002393.4:c.1091G>T

MDM4 · NP_002384.2:p.(Arg364Ile) · NM_002393.4

GRCh37: chr1:204518428 G>T · GRCh38: chr1:204549300 G>T

Gene: MDM4 Transcript: NM_002393.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MDM4

Transcript

NM_002393.4

Protein

NP_002384.2:p.(Arg364Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002393.4:c.1091G>T (p.Arg364Ile) is a missense variant in exon 11 of MDM4 encoding the RING finger domain.

2

This variant is absent from large population cohorts including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

3

Multiple in silico tools predict a deleterious effect: REVEL score 0.502 and BayesDel score 0.217 both exceed damaging thresholds, meeting PP3 at supporting strength. SpliceAI predicts no splicing impact (max delta 0.07).

4

No variant-specific functional studies, de novo observations, cosegregation data, case-control data, or ClinVar submissions were identified for this variant.

5

The variant lies in the MDM4 RING finger domain (residues 290–490) which is critical for MDM2 heterodimerization and p53 regulation, but no formal mutational hotspot has been established for PM1.

6

PVS1 is not applicable as this is a missense variant that does not fall into null variant categories under generic ClinGen SVI PVS1 framework.

7

With PM2_Supporting and PP3_Supporting, the variant receives two supporting-level pathogenic criteria. No benign criteria are met. By generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting criteria are insufficient to reach Likely Pathogenic (which requires at least one strong criterion + two supporting, or two moderate). The variant is classified as a Variant of Uncertain Significance (VUS).

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	N/A	Missense variant (p.Arg364Ile) does not fall into null variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 under generic ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	N/A	No different nucleotide change at codon 364 producing the same amino acid change (p.Arg364Ile) has been established as pathogenic. PS1 requires a known pathogenic variant with the same amino acid consequence from a different nucleotide substitution.
PS2	Not met	No de novo occurrence data identified for NM_002393.4:c.1091G>T. Targeted exploratory search of public databases and literature returned no de novo reports.
PS3	Not met	No variant-specific functional assay data identified for p.Arg364Ile. OncoKB classifies this variant as 'Unknown Oncogenic Effect'; no reviewed functional evidence is available. Exploratory literature search found no publications with direct experimental data for this variant.	oncokb
PS4	Not met	Variant is absent from ClinVar with no patient observations documented. No case-control association study or cohort prevalence data available. PM2 is met (absent from population databases) but this does not constitute PS4 evidence of enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
PS5	N/A	PS5 requires a same-residue pathogenic missense change with a different amino acid substitution (a stronger version of PM5). No same-residue pathogenic comparator variants exist; PM5 is not applicable, so PS5 is also not applicable.
PM1	Not met	Variant lies in the MDM4 RING finger domain (residues 290–490) which is functionally important for MDM2 heterodimerization and E3 ubiquitin ligase activity. However, no formal mutational hotspot analysis demonstrates a statistically significant enrichment of pathogenic missense variants in this domain under generic ACMG/AMP criteria.
PM2	Met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, representing large population cohorts (combined >250,000 alleles). Allele frequency is 0.0, meeting the generic ACMG PM2 threshold (<0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (codon 364) pathogenic missense comparator variants identified in ClinVar. Automated PM5 candidate harvesting returned zero candidates. PM5 cannot be applied without a confirmed pathogenic missense change at the same residue.
PM6	Not met	No assumed de novo evidence (without confirmed parentage) available for NM_002393.4:c.1091G>T. Exploratory search found no reports of this variant occurring de novo in any affected individual.
PP1	Not met	No family-based cosegregation data available. PP1 requires the variant to cosegregate with disease in multiple affected family members; no such studies include this variant.
PP2	Not met	MDM4 does not meet PP2 criteria: the gene does not have an established low rate of benign missense variation and a high proportion of pathogenic missense variants. MDM4 germline disease is emerging but not well-characterized enough to apply PP2 under generic ACMG/AMP.
PP3	Met	Multiple in silico tools predict a deleterious effect: REVEL score 0.502 (threshold ≥0.5 for damaging) and BayesDel score 0.217 (threshold >0.07 for damaging, noAF model). SpliceAI predicts no significant splicing impact (max delta 0.07). Two of three computational lines support pathogenicity.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data available for the proband harboring this variant. PP4 requires a highly specific phenotype or family history consistent with a single genetic etiology.
PP5	N/A	Variant is absent from ClinVar with no submissions from any submitter. PP5 requires a reputable source (e.g., clinical diagnostic laboratory) to have reported the variant as pathogenic, which has not occurred.	clinvar
BA1	Not met	Variant is absent from all gnomAD population cohorts (allele frequency 0.0), far below the BA1 threshold of >1% allele frequency in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from all gnomAD population cohorts (allele frequency 0.0), below the BS1 threshold of >0.3% allele frequency. Rarity supports pathogenicity rather than benign impact.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Variant has not been observed in any healthy adult individual in population databases. BS2 requires observation in healthy adults for a disorder with full penetrance expected at an early age, which cannot be assessed without such observations.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a neutral or benign effect for p.Arg364Ile. BS3 requires functional evidence showing no deleterious impact on protein function or splicing.
BS4	Not met	No family segregation data available. BS4 requires lack of segregation with disease in multiple affected family members — no such studies include this variant.
BP1	Not met	While MDM4 loss of function is supported as a germline disease mechanism (PVS1 gene context eligible), there is insufficient evidence that only truncating variants cause MDM4-related disease to apply BP1 to this missense variant under generic ACMG/AMP.
BP2	Not met	No observation of NM_002393.4:c.1091G>T in trans with a known pathogenic MDM4 variant. MDM4 is not associated with a recessive disorder; BP2 is unlikely to apply.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This is a single-nucleotide substitution.
BP4	Not met	Computational evidence does not suggest a benign impact. REVEL score 0.502 and BayesDel score 0.217 both predict a deleterious effect. Only SpliceAI (max delta 0.07) predicts no splicing impact. Multiple lines do not uniformly suggest no impact; BP4 is not met.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in any individual harboring this variant. BP5 cannot be applied in the absence of such data.
BP6	Not met	No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as benign or likely benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact. NM_002393.4:c.1091G>T is a missense variant (p.Arg364Ile), not synonymous.

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.