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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MBD4 encodes a DNA glycosylase that detects and repairs deaminated methyl-cytosines in DNA, using a methyl-CpG binding domain to anchor to methylated DNA and a glycosylase domain to carry out mismatch repair in CpG-rich regions. The protein also helps repress transcription from methylated gene promoters. MBD4 acts as a tumor suppressor, and its loss has been linked to colorectal cancer, acute myeloid leukemia, and uveal melanoma.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with allele frequency <=0.0001 for generic PM2.
Met, supporting: REVEL 0.658 meets the >=0.644 missense PP3 threshold calibrated by ClinGen SVI (PMID:36413997).
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) and PP3 (supporting) provide two supporting criteria, which do not satisfy a generic ACMG/AMP pathogenic, benign, or likely classification threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.658. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No governing MBD4 VCEP or gene-specific framework was available, so generic ACMG/AMP criterion definitions were used.
The variant is NM_001276270.2:c.1375T>A, encoding NP_001263199.1:p.(Phe459Ile), a missense substitution.
No identical-substitution comparator, eligible same-residue pathogenic comparator, or authoritative MBD4 critical-domain evidence was available; gene-level evidence supports loss of function rather than a predominantly missense mechanism.
No MBD4-specific VCEP or CSPEC framework was retrieved, so generic ACMG/AMP rules were used where applicable.
PS4, PP4, and BP5 lack the required patient-level or case-control evidence and are not assessed.
PP5 and BP6 are not met because ClinVar reports no exact-variant record and therefore provides no qualifying expert-panel assertion.
No criteria match.
PM2 is met at supporting strength. The variant is absent from the default all-comers gnomAD v2.1 and v4.1 datasets and from the available non-cancer subsets, satisfying the supplied generic PM2 supporting threshold of allele frequency <=0.0001. No governing VCEP or gene-specific specification was identified, so the generic SVI recommendation to use PM2 only at supporting strength applies.
generic_acmg_pm2: allele_frequency <= 0.0001; supporting_only
The variant is a missense substitution, NM_001276270.2:c.1375T>A (p.Phe459Ile), so PP3 was evaluated using the missense REVEL path only. REVEL is 0.658, meeting the generic ClinGen SVI supporting PP3 threshold of >=0.644 from the Pejaver et al. 2022 calibration (PMID:36413997). SpliceAI was not used because splice prediction is not the applicable computational path for a missense variant; BayesDel has no generic ACMG/ClinGen strength calibration.
Generic ClinGen SVI REVEL calibration: PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
PP2 is not met because the available MBD4 gene-level evidence supports loss of function as the germline disease mechanism, not a disease mechanism predominantly involving missense variation. The available record does not establish both that pathogenic missense variation is a common MBD4 disease mechanism and that benign missense variation is uncommon.
Generic ACMG/AMP PP2: missense variants are a common mechanism of disease and benign missense variation is uncommon in the gene.
PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion. The available ClinVar search reports no result for NM_001276270.2:c.1375T>A, so no qualifying expert-panel assertion exists to support PP5.
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
BA1 is not met. The variant is absent from the default all-comers gnomAD v2.1 and v4.1 datasets, and also absent from the available non-cancer subsets; therefore no population allele frequency reaches the generic BA1 stand-alone threshold of >=0.05. No governing VCEP or gene-specific specification was identified, so the generic ACMG/AMP threshold applies.
generic_acmg_ba1: allele_frequency >= 0.05
BS1 is not met. The variant is absent from the default all-comers gnomAD v2.1 and v4.1 datasets, and also absent from the available non-cancer subsets; thus no observed allele frequency reaches the generic BS1 threshold of >=0.01. No governing VCEP or gene-specific specification was identified, so the generic threshold applies.
generic_acmg_bs1: allele_frequency >= 0.01
The variant is a missense substitution, NM_001276270.2:c.1375T>A (p.Phe459Ile), so BP4 was evaluated using the missense REVEL path only. REVEL is 0.658, which is above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from the Pejaver et al. 2022 calibration (PMID:36413997); therefore BP4 is not met. SpliceAI was not used because splice prediction is not the applicable computational path for a missense variant, and the BayesDel score is not interpretable under generic ACMG strength calibration.
Generic ClinGen SVI REVEL calibration: BP4 supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign assertion. The available ClinVar search reports no result for NM_001276270.2:c.1375T>A, so no qualifying expert-panel assertion exists to support BP6.
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
PS1 cannot be assessed. The variant is NP_001263199.1:p.(Phe459Ile), but no established pathogenic or likely pathogenic report of the identical amino-acid substitution was identified in the available clinical or literature evidence. ClinVar returned no record for NM_001276270.2:c.1375T>A, and no PMID-linked variant report was available.
Generic ACMG/AMP PS1: same amino-acid change as an established pathogenic variant.
No proband-level de novo evidence is available: the case materials do not document parental genotypes, confirmed maternity and paternity, or testing showing that NM_001276270.2:c.1375T>A is absent in both parents. Therefore PS2 cannot be assessed.
PS3 cannot be assessed because the available case evidence contains no variant-specific functional study for NM_001276270.2:c.1375T>A (NP_001263199.1:p.(Phe459Ile)). No validated assay result, quantitative activity measurement, assay controls, or other experimental demonstration of abnormal MBD4 function was identified. Gene-level loss-of-function literature does not establish the effect of this specific missense variant and is insufficient for PS3.
generic ACMG/AMP functional evidence requires well-established functional studies showing a damaging effect; variant-specific assay data are absent
No case series, affected-carrier count, control comparison, odds ratio, or other case-control enrichment measure is available for NM_001276270.2:c.1375T>A. Therefore the generic PS4 disease-enrichment criterion cannot be assessed.
Generic ACMG/AMP PS4 requires statistically significant enrichment of the variant in affected individuals compared with appropriate controls; no applicable MBD4 VCEP specification was retrieved.
PM1 cannot be assessed. No governing MBD4 VCEP specification was available, and vcep_materials.json contained no MBD4 domain_tables entry to serve as the authoritative complete domain list. Therefore residue 459 cannot be confirmed as lying in an approved critical functional domain. The independent hotspot result was negative.
Generic ACMG/AMP PM1: variant located in a mutational hotspot and/or critical and well-established functional domain without benign variation.
PM3 requires evidence that the variant is present in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive disorder, or other qualifying affected-proband phase observations under the generic ACMG/AMP framework (Richards et al. 2015, PMID:25741868). The available case evidence contains no affected-proband observations, second pathogenic allele, phase determination, segregation data, or inheritance information for NM_001276270.2:c.1375T>A (MBD4 p.Phe459Ile). Therefore PM3 cannot be assessed rather than being considered absent or not met.
generic_acmg_pm3: requires_qualifying_affected_proband_evidence_with_pathogenic_variant_in_trans
PM5 cannot be assessed. The variant affects MBD4 residue Phe459, but no alternate missense variant at residue 459 with an established pathogenic or likely pathogenic classification was identified. The PM5 candidate record contains zero same-residue candidates and does not establish classic PM5 semantics.
Generic ACMG/AMP PM5: novel missense change at an amino-acid residue where a different missense change is pathogenic.
No suspected de novo evidence without parental testing is reported. The available materials do not describe a proband with the variant, a consistent phenotype, or circumstances supporting a presumed de novo event when parental genotypes are unavailable. Therefore PM6 cannot be assessed.
No familial segregation data are available. The case materials do not identify affected or unaffected relatives carrying or lacking NM_001276270.2:c.1375T>A, and they provide no informative meioses or phenotype concordance suitable for PP1 assessment.
No individual-level phenotype, clinical diagnosis, or phenotype-specific disease description is supplied for the carrier of NM_001276270.2:c.1375T>A. The gene-level literature context does not establish that this variant is present in a patient with a highly specific phenotype, so generic PP4 cannot be assessed.
Generic ACMG/AMP PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single-gene etiology; no applicable MBD4 VCEP specification was retrieved.
BS2 cannot be assessed from the available evidence. The gnomAD records establish absence of the variant from the queried population datasets but provide no documented unaffected adult homozygotes or other healthy individuals carrying the variant. Because no homozygote or healthy-carrier observations are available, the BS2 criterion remains unassessed rather than being inferred from population absence.
generic_acmg_bs2: requires_observation_in_healthy_adults_or_unaffected_adult_homozygotes
BS3 cannot be assessed because the available case evidence contains no variant-specific functional study demonstrating that NM_001276270.2:c.1375T>A (NP_001263199.1:p.(Phe459Ile)) preserves normal MBD4 function. No validated assay, appropriate controls, quantitative normal-function result, or physiologically relevant benign readout was identified. The absence of a damaging assay result is not evidence of preserved function, so BS3 cannot be applied.
generic ACMG/AMP functional evidence requires well-established functional studies showing no damaging effect; variant-specific normal-function assay data are absent
No non-segregation evidence is available. The case materials do not document unaffected relatives who were appropriately tested and shown to carry NM_001276270.2:c.1375T>A, nor do they establish that the variant fails to segregate with disease in an informative family.
BP1 cannot be assessed. Although the available MBD4 gene-level evidence supports loss of function as a germline disease mechanism, it does not establish that MBD4 disease is caused primarily by truncating variants or provide a sufficiently characterized disease variant spectrum to apply BP1 to this missense variant.
Generic ACMG/AMP BP1: missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires a documented observation of the variant in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic variant, with the applicable inheritance and phase context under the generic ACMG/AMP framework (Richards et al. 2015, PMID:25741868). The available case evidence contains no second variant, pathogenic comparator, phase determination, affected or unaffected individual context, or inheritance information for NM_001276270.2:c.1375T>A (MBD4 p.Phe459Ile). Therefore BP2 cannot be assessed rather than being considered absent or not met.
generic_acmg_bp2: requires_qualifying_phase_resolved_observation_with_pathogenic_variant
No patient-level evidence is available showing that a confirmed alternative molecular cause explains the relevant phenotype in an individual carrying NM_001276270.2:c.1375T>A. The absence of ClinVar and the absence of variant-specific literature do not establish BP5, so this criterion cannot be assessed.
Generic ACMG/AMP BP5 requires a pathogenic variant in an alternative gene that explains the patient's phenotype; no applicable MBD4 VCEP specification was retrieved.
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
deterministic_prefilter: requires_synonymous
Every interpreted variant in MBD4, mapped onto the exon structure of NM_001276270.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, NM_001276270.2:c.1375T>A (p.Phe459Ile), so PP3 was evaluated using the missense REVEL path only. REVEL is 0.658, meeting the generic ClinGen SVI supporting PP3 threshold of >=0.644 from the Pejaver et al. 2022 calibration (PMID:36413997). SpliceAI was not used because splice prediction is not the applicable computational path for a missense variant; BayesDel has no generic ACMG/ClinGen strength calibration.
Generic ClinGen SVI REVEL calibration: PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
The variant is a missense substitution, NM_001276270.2:c.1375T>A (p.Phe459Ile), so BP4 was evaluated using the missense REVEL path only. REVEL is 0.658, which is above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from the Pejaver et al. 2022 calibration (PMID:36413997); therefore BP4 is not met. SpliceAI was not used because splice prediction is not the applicable computational path for a missense variant, and the BayesDel score is not interpretable under generic ACMG strength calibration.
Generic ClinGen SVI REVEL calibration: BP4 supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.658. BayesDel score = 0.186614.
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.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.658. BayesDel score = 0.186614.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.