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MDM4c.1091G>TUncertain significance
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Variant interpretation report

MDM4 c.1091G>T, p.(Arg364Ile)

NM_002393.4:c.1091G>T NP_002384.2:p.(Arg364Ile) 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 MDM4

No gene-level summary was recorded for this case.

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
PM2Supporting
PM2 · supporting

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%).

PP3Supporting
PP3 · supporting

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.

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: PM2 supporting, PP3 supporting; combination = 2 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.

SpliceAI score
0.070 maximum delta

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

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MDM4, a negative regulator of the p53 tumor suppressor, is altered by amplification and overexpression in various cancer types including breast cancer

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.

27 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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

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

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).

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

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.

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

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).

Met · 2

PM2 SupportingVariant 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles). Absent from gnomAD v4.1 (0 alleles). Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.502 (damaging). BayesDel (noAF): 0.217 (damaging). SpliceAI max delta: 0.07 (no splicing impact).
Still missing
  • REVEL score is borderline (0.502 at the 0.5 threshold). HCI Prior not available for MDM4.
Sources
revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS2 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. Details ▾Hide ▴
Evidence considered
  • Exploratory search of denovo-db and literature returned no de novo observations for this variant.
Still missing
  • No de novo confirmation with maternity and paternity testing available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No functional assays (ubiquitination
  • co-immunoprecipitation
  • transcriptional activation) testing p.Arg364Ile were found.
Still missing
  • No in vitro or in vivo functional studies testing the specific effect of p.Arg364Ile on MDM4 protein function.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar (no submissions). Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada.
Still missing
  • No affected individual case counts or case-control comparison data available.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • RING domain is functionally critical
  • but no curated hotspot analysis or VCEP-defined domain exists for MDM4.
Still missing
  • No curated database of pathogenic MDM4 missense variants demonstrating enrichment in the RING domain versus the rest of the gene.
PM6 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. Details ▾Hide ▴
Evidence considered
  • No de novo observations in any database or literature source.
Still missing
  • No de novo reports
  • even without confirmed parentage.
PP1 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. Details ▾Hide ▴
Evidence considered
  • No cosegregation data available in ClinVar submissions or literature.
Still missing
  • No family studies or pedigree data available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • No established gene-level PP2 designation for MDM4. Germline MDM4 disease spectrum is still being characterized.
Still missing
  • No formal gene-level constraint metrics (e.g.
  • missense Z-score
  • gnomAD constraint) evaluated for PP2 applicability.
PP4 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. Details ▾Hide ▴
Evidence considered
  • No phenotypic data available for the individual carrying this variant.
Still missing
  • Patient phenotype and family history not provided.
BA1 Variant is absent from all gnomAD population cohorts (allele frequency 0.0), far below the BA1 threshold of >1% allele frequency in any population. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0.0. gnomAD v4.1 AF: 0.0. gnomAD-Canada AF: 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0.0. gnomAD v4.1 AF: 0.0. gnomAD-Canada AF: 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • no healthy adult carriers identified.
Still missing
  • No observations in any population cohort to assess BS2.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • No functional studies testing p.Arg364Ile for benign effect identified.
Still missing
  • No functional assays demonstrating normal MDM4 protein function for this variant.
BS4 No family segregation data available. BS4 requires lack of segregation with disease in multiple affected family members — no such studies include this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data identified.
Still missing
  • No pedigree or cosegregation analysis available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • PVS1 gene context confirms LOF mechanism support but does not establish that primarily truncating variants cause disease.
Still missing
  • No formal evidence that MDM4 disease is exclusively or primarily caused by truncating variants.
BP2 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. Details ▾Hide ▴
Evidence considered
  • No biallelic observations
  • MDM4 disease is not recessive.
Still missing
  • No observations in trans.
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.502 (damaging). BayesDel: 0.217 (damaging). SpliceAI: 0.07 (no splicing impact). Majority of in silico tools favor deleterious effect.
Sources
revelbayesdelspliceai ↗
BP5 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. Details ▾Hide ▴
Evidence considered
  • No cases with an alternate molecular finding reported.
Still missing
  • No data on alternate molecular diagnoses in variant carriers.
BP6 No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as benign or likely benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • ClinVar: no submissions
  • no benign classification from any source.
Sources
clinvar ↗
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense 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). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution classified as 'other' bucket — does not meet PVS1 null variant criteria.
Sources
pvs1_generic_framework ↗
PS1 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic comparator identified in ClinVar or literature.
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search yielded zero same-residue pathogenic comparators.
PP5 N/AVariant 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. Details ▾Hide ▴
Evidence considered
  • ClinVar: no submissions
  • no classification.
Sources
clinvar ↗
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. NM_002393.4:c.1091G>T is a missense variant (p.Arg364Ile), not synonymous. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴
Evidence considered
  • No same-residue (codon 364) pathogenic missense comparator identified.

Identifiers

Gene
MDM4
Transcript
NM_002393.4
Coding (HGVS c.)
NM_002393.4:c.1091G>T
Protein (HGVS p.)
NP_002384.2:p.(Arg364Ile)
GRCh38
chr1:204549300 G>T
GRCh37
chr1:204518428 G>T

Gene diagram

Every interpreted variant in MDM4, mapped onto the exon structure of NM_002393.4. Select a row to find it on the plot.

MDM4NM_002393.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -34 bp
0.070
SpliceAI acceptor gainat +25 bp
0.020
SpliceAI donor lossat -138 bp
0.020
SpliceAI donor gainat +384 bp
0.000
Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.010

Other predictors

REVEL
0.502
BayesDel
0.217

How the predictions were used

PP3 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.502 (damaging). BayesDel (noAF): 0.217 (damaging). SpliceAI max delta: 0.07 (no splicing impact).
Still missing
  • REVEL score is borderline (0.502 at the 0.5 threshold). HCI Prior not available for MDM4.
Sources
revelbayesdelspliceai ↗
BP4 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.502 (damaging). BayesDel: 0.217 (damaging). SpliceAI: 0.07 (no splicing impact). Majority of in silico tools favor deleterious effect.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. NM_002393.4:c.1091G>T is a missense variant (p.Arg364Ile), not synonymous. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.502. BayesDel score = 0.216576.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.070 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.502. BayesDel score = 0.216576.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MDM4, a negative regulator of the p53 tumor suppressor, is altered by amplification and overexpression in various cancer types including breast cancer

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.