No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Met (stand-alone benign): gnomAD v4.1 allele frequency of 1.01% exceeds the 1% BA1 threshold.
Met (strong benign): allele frequency of 1.01% exceeds the 0.3% BS1 threshold.
Met (supporting): REVEL score 0.218 is below the BP4 benign cutoff of 0.250.
No MBD4-specific VCEP/CSPEC framework was available, so generic ACMG/AMP 2015 criteria applied; BA1 (stand-alone benign) alone establishes Benign, with BS1 and BP4 concordant.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 16,365 / 1,614,030 alleles. Recorded AF 0.0101392. Recorded homozygote count 84.
This variant is present in gnomAD v2.1 (AF= 0.00721936; MAF= 0.72194%, 2041/282712 alleles, homozygotes = 10) and has highest observed frequency in the Remaining individuals population (AF= 0.0112282; MAF= 1.12282%, 81/7214 alleles, homozygotes = 1); grpmax FAF= 0.0109125.
This variant is present in gnomAD-Canada v1.0 (AF= 0.010315995222065371, 190/18418 alleles, homozygotes = 2).
Recorded REVEL score: 0.218. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Benign · 3 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MBD4, a DNA glycosylase, is infrequently altered in cancer.
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: 3 met · 4 not met · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Generic ACMG/AMP fallback was used because no applicable MBD4-specific VCEP/CSPEC framework was found.
No codon-, residue-, domain-, hotspot-, or missense-mechanism criterion in this requested group could be established from the validated case evidence bundle.
No applicable MBD4-specific ClinGen/VCEP specification was identified, so generic ACMG/AMP population rules were used.
The concordant high frequency across gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada supports BA1 and BS1 and excludes PM2.
Homozygote counts are recorded but are not converted to BS2 because healthy-adult phenotype ascertainment and a validated MBD4 disease model are unavailable.
No criteria match.
The variant is too common for a rare, highly penetrant Mendelian disease under the generic fallback population thresholds used for this case. gnomAD v4.1 reports AF 0.0101392 (1.01392%), with a maximum population AF of 0.0121222 (1.21222%) in European non-Finnish individuals; gnomAD v2.1 and gnomAD-Canada independently also show AFs of approximately 0.72% and 1.03%, respectively. The gnomAD v4.1 overall AF and maximum population AF exceed the 1% BA1 threshold.
Generic ACMG/AMP fallback: BA1 if population allele frequency is >1% in an appropriate reference population; use the highest credible observed population frequency and consider ancestry-specific maxima.
Population frequency is above the generic fallback BS1 threshold. gnomAD v4.1 reports AF 1.01392% overall and 1.21222% in the European non-Finnish population; gnomAD v2.1 and gnomAD-Canada provide concordant frequencies of 0.72194% and 1.03160%. These observations exceed the case's generic non-VCEP BS1 threshold of 0.3%. The frequency is sufficiently high that BS1 is supported independently of any disease-specific prevalence or penetrance estimate.
Generic ACMG/AMP fallback: BS1 if the allele frequency is greater than the expected maximum for a disorder; in this case, absent a disease-specific model, the operational non-VCEP threshold is >0.3%.
BP4 is met at supporting strength. This is a missense variant and no MBD4-specific VCEP specification was available, so the generic non-VCEP REVEL-only rule applies. REVEL is 0.218, below the calibrated BP4 cutoff of 0.250. SpliceAI and BayesDel are not additionally counted, preventing duplicate computational evidence and use of an uncalibrated BayesDel threshold.
generic_acmg_non_vcep_missense: REVEL <0.250 => BP4_supporting; one mechanism only
PM2 is not met because the variant is common in multiple population datasets rather than absent or sufficiently rare. gnomAD v4.1 reports AF 1.01392% overall and 1.21222% in the maximum population group, with 84 homozygotes; gnomAD v2.1 reports AF 0.72194% with 10 homozygotes; and gnomAD-Canada reports AF 1.03160% with 2 homozygotes. These frequencies are far above the generic fallback rarity threshold of <0.1%.
Generic ACMG/AMP fallback: PM2 requires absence or rarity below 0.1% in appropriate population databases; this variant is not rare.
PP3 is not met. This is a missense variant, so the applicable generic non-VCEP computational path is REVEL alone. The REVEL score of 0.218 is below the PP3 threshold (>0.750) and instead falls below the calibrated BP4 threshold. SpliceAI (max delta 0.00) and BayesDel (-0.358238) were not used to independently assess PP3 because the generic framework prohibits applying splice-path evidence to a missense variant and BayesDel has no verified usable calibration in this pipeline.
generic_acmg_non_vcep_missense: REVEL >0.750 => PP3_supporting; REVEL <0.250 => BP4_supporting; one mechanism only
The exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Apply PP5 only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
The exact variant has no ClinVar expert-panel Benign or Likely benign classification.
Apply BP6 only to an exact-variant ClinVar expert-panel Benign or Likely benign classification.
The variant is NP_001263199.1:p.(Ile358Thr), but the case bundle contains no validated report of the same amino-acid change as pathogenic or likely pathogenic. The available paper extracts do not mention MBD4 or this variant, and ClinVar submissions are benign or likely benign; those classifications were not used as evidence for PS1. Therefore, PS1 cannot be established from this bundle.
PS1 requires a well-established pathogenic variant that results in the same amino-acid change as the assessed variant.
No proband-level de novo observation with confirmed maternity and paternity, parental genotypes, or validated parental absence of NM_001276270.2:c.1073T>C is documented in the case-evidence bundle. Therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed maternity and paternity; without parental and proband evidence, assess as not_assessed.
No applicable MBD4-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle contains no validated functional assay demonstrating that MBD4 p.Ile358Thr causes a damaging effect. OncoKB reports no variant-specific reviewed functional evidence, and the functional-theme papers available in the pre-computed paper extracts do not report this variant or MBD4 assay results. Therefore PS3 cannot be assigned.
PS3 requires well-established functional studies supportive of a damaging effect. In the absence of a gene-specific specification, assay validity, controls, biological relevance, and reproducibility must be demonstrated before assigning strength.
No case-control or cohort data demonstrate enrichment of MBD4 c.1073T>C (p.Ile358Thr) among affected individuals relative to controls.
Generic ACMG/AMP PS4: significantly increased prevalence in affected individuals compared with controls requires statistically interpretable, phenotype-defined case-control evidence.
No applicable MBD4-specific VCEP or CSPEC framework is present. vcep_materials.json has an empty domain_tables object, so there is no authoritative approved critical-domain list to check against residue 358. The bundle also provides no independently validated critical functional-domain or hotspot evidence for MBD4 residue 358.
PM1 requires a variant located in a mutational hot spot or critical and well-established functional domain, without benign variation; under this case's instructions, an available gene-specific domain table would be authoritative.
No ClinGen CSPEC or gene-specific framework was available, so the generic ACMG/AMP framework was used. The case bundle contains no affected-proband observation, second pathogenic or likely pathogenic MBD4 variant, phase determination, or inheritance information demonstrating that NM_001276270.2:c.1073T>C (p.Ile358Thr) is in trans with a pathogenic variant in an affected individual. The available population and ClinVar records do not establish PM3 and cannot substitute for phase or affected-proband evidence.
Generic ACMG/AMP PM3: for a recessive disorder, the variant is observed in trans with a pathogenic variant in an affected individual; phase and clinical context must be established.
The assessed change is p.Ile358Thr. The case bundle contains no verified pathogenic or likely pathogenic missense comparator at the same residue, and pm5_candidates.json reports zero harvested candidates while explicitly stating that classic same-residue PM5 semantics could not be safely confirmed. PM5 therefore cannot be applied from the available evidence.
PM5 requires a novel missense change at an amino-acid residue where a different missense change is established as pathogenic.
No case or literature evidence documents NM_001276270.2:c.1073T>C as apparently de novo without confirmed maternity and paternity. The available literature extracts do not contain this variant or a relevant family observation. Therefore PM6 cannot be assessed.
Generic ACMG/AMP PM6 applies to an apparently de novo occurrence when maternity and paternity are not confirmed; absent a documented affected case and de novo observation, assess as not_assessed.
No affected relatives, informative meioses, phase data, or family segregation results for NM_001276270.2:c.1073T>C are provided. The available evidence is insufficient to evaluate co-segregation with disease, so PP1 is not assessed.
Generic ACMG/AMP PP1 requires co-segregation of the variant with disease in multiple affected family members, interpreted using informative meioses and phenotype certainty; no family data are available here.
No MBD4-specific framework or validated missense-spectrum analysis is available to establish both PP2 requirements: that missense variation is a recognized disease mechanism for MBD4 and that benign missense variation is unusually uncommon. The bundle supports MBD4 loss-of-function context in a separate gene-context artifact, but that does not by itself establish PP2 for this missense variant. PP2 is not applied.
PP2 requires a missense mechanism in the relevant gene and a low rate of benign missense variation in that gene; both components must be supported independently.
No proband phenotype, diagnostic testing context, or evidence that the observed phenotype is highly specific for an MBD4-related disorder is provided.
Generic ACMG/AMP PP4: a patient's phenotype or family history must be highly specific for disease with a single genetic etiology.
The variant is observed in homozygous individuals in gnomAD v4.1 (84 overall; 71 in European non-Finnish individuals), gnomAD v2.1 (10 overall), and gnomAD-Canada (2). However, the case bundle does not establish that these individuals were healthy adults assessed for the relevant MBD4-associated phenotype, and it does not provide a validated MBD4 inheritance model, disease prevalence, or penetrance estimate that would define how homozygosity should be interpreted. Population-database homozygote counts alone therefore do not satisfy the generic BS2 requirement for observations in healthy adults.
Generic ACMG/AMP BS2 requires observation in healthy adults in the genotype configuration relevant to the disease model; an unphenotyped population-database homozygote count is insufficient by itself.
No applicable MBD4-specific VCEP framework was retrieved, so the generic ACMG/AMP framework applies. The case bundle contains no validated functional assay showing that MBD4 p.Ile358Thr has a normal or non-damaging effect. OncoKB reports no variant-specific reviewed functional evidence, and the available functional-theme papers do not report this variant or relevant MBD4 assay results. Therefore BS3 cannot be assigned.
BS3 requires well-established functional studies showing no damaging effect on protein function or a validated normal functional result. In the absence of a gene-specific specification, assay validity, controls, biological relevance, and reproducibility must be demonstrated before assigning strength.
No unaffected relatives known to be at risk have been tested for NM_001276270.2:c.1073T>C, and no reliable non-segregation result is documented. The absence of family data prevents evaluation of BS4.
Generic ACMG/AMP BS4 requires lack of segregation in affected families, such as the variant being observed in unaffected relatives when disease status is reliable; without informative family data, assess as not_assessed.
The bundle contains evidence consistent with MBD4 loss-of-function disease biology, but it does not establish that MBD4-related disease is caused primarily by truncating variants with missense variants not known to cause disease. The available case-specific literature extracts contain no relevant MBD4 variant-spectrum evidence. BP1 is therefore not applied.
BP1 requires a missense variant in a gene for which primarily truncating variants are known to cause disease and for which missense variants are not a known disease mechanism.
No ClinGen CSPEC or gene-specific framework was available, so the generic ACMG/AMP framework was used. The case bundle contains no documented affected or unaffected individual carrying NM_001276270.2:c.1073T>C (p.Ile358Thr) with another pathogenic variant, and no phase information showing the variants are in trans or cis in a context that would support BP2. Therefore BP2 cannot be assessed from the available evidence.
Generic ACMG/AMP BP2: assess only when the variant is observed with another pathogenic variant in a documented allelic context (cis or trans) relevant to the disorder and inheritance model; phase and clinical context are required.
No affected individual, phenotype, or independently established molecular diagnosis is provided to evaluate whether this variant occurs with an alternate cause of disease.
Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001276270.2:c.1073T>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Ile358Thr). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001276270.2:c.1073T>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Ile358Thr). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001276270.2:c.1073T>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Ile358Thr). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001276270.2:c.1073T>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Ile358Thr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
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 |
|---|
| European (non-Finnish)14304 / 1,179,986 | 0.01271 hom |
| Middle Eastern66 / 6,062 | 0.0113 hom |
| Remaining individuals662 / 62,506 | 0.0115 hom |
| Ashkenazi Jewish266 / 29,600 | 0.009 |
| Amish7 / 912 | 0.0077 |
| Admixed American460 / 60,030 | 0.00773 hom |
| European (Finnish)185 / 64,012 | 0.0029 |
| South Asian258 / 91,082 | 0.00282 hom |
| African/African American156 / 75,002 | 0.0021 |
| East Asian1 / 44,838 | 2.2e-05 |
| Remaining individuals81 / 7,214 | 0.0111 hom |
| European (non-Finnish)1425 / 129,070 | 0.0118 hom |
| Ashkenazi Jewish106 / 10,368 | 0.01 |
| Admixed American230 / 35,420 | 0.00651 hom |
| South Asian88 / 30,612 | 0.0029 |
| European (Finnish)68 / 25,120 | 0.0027 |
| African/African American43 / 24,954 | 0.0017 |
This variant is present in gnomAD v4.1 (AF= 0.0101392; MAF= 1.01392%, 16365/1614030 alleles, homozygotes = 84) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0121222; MAF= 1.21222%, 14304/1179986 alleles, homozygotes = 71); grpmax FAF= 0.0119554.
This variant is present in gnomAD v2.1 (AF= 0.00721936; MAF= 0.72194%, 2041/282712 alleles, homozygotes = 10) and has highest observed frequency in the Remaining individuals population (AF= 0.0112282; MAF= 1.12282%, 81/7214 alleles, homozygotes = 1); grpmax FAF= 0.0109125.
This variant is present in gnomAD-Canada v1.0 (AF= 0.010315995222065371, 190/18418 alleles, homozygotes = 2).
BP4 is met at supporting strength. This is a missense variant and no MBD4-specific VCEP specification was available, so the generic non-VCEP REVEL-only rule applies. REVEL is 0.218, below the calibrated BP4 cutoff of 0.250. SpliceAI and BayesDel are not additionally counted, preventing duplicate computational evidence and use of an uncalibrated BayesDel threshold.
generic_acmg_non_vcep_missense: REVEL <0.250 => BP4_supporting; one mechanism only
PP3 is not met. This is a missense variant, so the applicable generic non-VCEP computational path is REVEL alone. The REVEL score of 0.218 is below the PP3 threshold (>0.750) and instead falls below the calibrated BP4 threshold. SpliceAI (max delta 0.00) and BayesDel (-0.358238) were not used to independently assess PP3 because the generic framework prohibits applying splice-path evidence to a missense variant and BayesDel has no verified usable calibration in this pipeline.
generic_acmg_non_vcep_missense: REVEL >0.750 => PP3_supporting; REVEL <0.250 => BP4_supporting; one mechanism only
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001276270.2:c.1073T>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Ile358Thr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.218. BayesDel score = -0.358238.
7 paper records 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.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants, paragraph 3
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.
This variant is present in gnomAD v4.1 (AF= 0.0101392; MAF= 1.01392%, 16365/1614030 alleles, homozygotes = 84) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0121222; MAF= 1.21222%, 14304/1179986 alleles, homozygotes = 71); grpmax FAF= 0.0119554.
This variant is present in gnomAD v2.1 (AF= 0.00721936; MAF= 0.72194%, 2041/282712 alleles, homozygotes = 10) and has highest observed frequency in the Remaining individuals population (AF= 0.0112282; MAF= 1.12282%, 81/7214 alleles, homozygotes = 1); grpmax FAF= 0.0109125.
This variant is present in gnomAD-Canada v1.0 (AF= 0.010315995222065371, 190/18418 alleles, homozygotes = 2).
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 1299953)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.218. BayesDel score = -0.358238.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MBD4, a DNA glycosylase, is infrequently altered in cancer.
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.