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 (Supporting): gnomAD v4.1 frequency 0.02258% is below the 0.1% rare-variant threshold, though the variant is not absent.
Met (Supporting): SpliceAI maximum delta 0.00 is below the <0.10 BP4 threshold, supporting no predicted splice impact.
Not met: one pathogenic supporting criterion (PM2) and one benign supporting criterion (BP4) fall short of any ACMG/AMP 2015 combination threshold, leaving the variant a VUS.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 363 / 1,607,956 alleles. Recorded AF 0.000225752. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000146547; MAF= 0.01465%, 40/272950 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000290951; MAF= 0.02910%, 2/6874 alleles, homozygotes = 0); grpmax FAF= 0.00041979.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Uncertain significance.
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).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 11 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No segregation or de novo criterion was applied because the case bundle contains no proband-parent testing, pedigree, meiosis, affected-relative, or unaffected-relative evidence.
The bundle reports no applicable MBD4-specific VCEP/CSPEC framework, so generic ACMG/AMP rules were used.
The available paper extracts concern unrelated neonatal-screening policy and general variant-interpretation guidance; neither reports this variant or relevant family evidence.
Neither PM3 nor BP2 can be assessed because the supplied evidence contains no allelic phase, affected-proband, co-occurring pathogenic-variant, or inheritance observations.
No applicable MBD4 ClinGen CSPEC/VCEP framework was identified, so generic ACMG/AMP population criteria were used.
The variant is rare but not absent in gnomAD, has no observed homozygotes, and is far below BA1 and BS1 frequency thresholds.
Population evidence supports PM2 at supporting strength only; it does not support BA1, BS1, or BS2.
No criteria match.
The variant is rare in broad population datasets and is below the operational generic PM2 threshold of 0.1%: gnomAD v4.1 AF 0.02258% with grpmax FAF 0.026455%, and gnomAD v2.1 AF 0.01465% with grpmax FAF 0.041979%. It is not absent, so this is rare-variant PM2-supporting evidence rather than an absence claim.
Generic ACMG/AMP PM2: absent or sufficiently rare in population databases for the disease context; with no applicable gene-specific specification, this assessment uses a <0.1% operational threshold and applies PM2 at supporting strength for a rare but non-absent allele.
BP4 is met at supporting strength. No MBD4 VCEP/CSPEC PP3/BP4 specification is available. This is a non-missense variant, so the generic splice-prediction path uses SpliceAI rather than REVEL. SpliceAI maximum delta is 0.00, below the <0.10 BP4 supporting threshold.
generic_spliceai: BP4_supporting if max_delta < 0.10
PVS1 is not met. The MANE Select transcript NM_001276270.2 places this substitution at c.-1, one nucleotide upstream of the coding start (c.1); it is therefore a 5′-UTR/Kozak-context change, not a nonsense, frameshift, initiation-codon, or canonical intronic ±1/2 splice-site variant. The normalized consequence is p.(=), and SpliceAI reports no predicted splice effect (maximum delta 0.00). Thus no premature termination codon, exon loss, NMD prediction, or protein-length change is established. MBD4 loss of function may be a disease mechanism, but that gene-level eligibility does not convert this non-null variant consequence into PVS1 evidence.
ClinGen SVI generic PVS1 recommendations (PMC6185798): apply only to a qualifying predicted null variant in a gene where loss of function is an established disease mechanism; c.-1G>A is not a canonical intronic splice-site or initiation-codon variant.
PP3 is not met. No MBD4 VCEP/CSPEC PP3/BP4 specification is available, so the generic splice-prediction path applies to this non-missense variant. SpliceAI maximum delta is 0.00, which does not exceed the >0.20 PP3 supporting threshold. PP3 is also not used to duplicate the splice-prediction evidence considered for the canonical-splice PVS1 assessment.
generic_spliceai: PP3_supporting if max_delta > 0.20; not met at 0.00; do not duplicate PVS1 splice-prediction evidence
The exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification. The two available exact-variant submissions are uncertain-significance, single-submitter clinical laboratory assertions.
PP5 is permitted only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and aggregate labels do not qualify.
The variant is present in gnomAD v4.1 at 0.000225752 (0.02258%; 363/1,607,956 alleles), with a maximum group frequency of 0.00026455, far below the generic BA1 threshold of 1%. It therefore does not meet BA1.
Generic ACMG/AMP BA1: stand-alone benign evidence requires an allele frequency greater than 1% in a large population database, absent a gene-specific specification.
The highest reported population frequency is 0.000289924 (0.02899%) in the gnomAD v4.1 European non-Finnish population, and the maximum group frequency is 0.00026455. These values are below the operational generic BS1 threshold of 0.3%, so BS1 is not met.
Generic ACMG/AMP BS1: allele frequency greater than the disease-appropriate maximum credible frequency can support benign evidence; in this generic operational framework, BS1 is triggered at >0.3% when no gene-specific threshold exists.
No homozygotes were observed in gnomAD v2.1 (40 alternate alleles; 0 homozygotes) or gnomAD v4.1 (363 alternate alleles; 0 homozygotes). The available population data therefore do not provide BS2 evidence for occurrence of the variant in healthy adults as homozygotes.
Generic ACMG/AMP BS2: observation of the variant in healthy adults as homozygotes, or as hemizygotes for an X-linked condition, can support benign evidence; no such observation is present here.
The exact variant has no ClinVar expert-panel Benign or Likely benign classification. The two available exact-variant submissions are uncertain-significance, single-submitter clinical laboratory assertions.
BP6 is permitted only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions and aggregate labels do not qualify.
No proband-level de novo evidence is provided. The case bundle contains no parental genotypes, parental testing results, maternity/paternity confirmation, or statement that the variant is absent in both unaffected parents; therefore PS2 cannot be assessed.
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with confirmed maternity and paternity; strength depends on confirmation and phenotype evidence.
No validated variant-specific functional assay evidence was identified for NM_001276270.2:c.-1G>A. The available case bundle contains no RNA, splicing, protein, enzymatic, cellular, or other experimental result for this variant, and computational splice prediction is not sufficient to establish PS3. Therefore PS3 cannot be assessed.
No variant-specific affected-case series, case-control comparison, or statistically interpretable enrichment data were provided for NM_001276270.2(MBD4):c.-1G>A.
Generic ACMG/AMP fallback: PS4 requires increased prevalence of the variant in affected individuals compared with controls; no MBD4-specific specification was retrieved.
No applicable MBD4-specific VCEP or gene framework was available, so the generic ACMG/AMP PM3 concept was considered. The bundle contains no affected-proband observations, no confirmed pathogenic or likely pathogenic allele in trans, and no phase or inheritance information establishing recessive disease for this case. PM3 therefore cannot be assessed.
No unconfirmed de novo occurrence is reported for this variant. The bundle contains no parental history, parental genotypes, or clinical case description establishing a likely de novo event; PM6 therefore cannot be assessed.
Generic ACMG/AMP PM6: assumed de novo, without confirmation of paternity and maternity, in a patient with the disease and no family history.
No informative affected or unaffected relatives, segregation observations, or meioses are reported. There is consequently no evidence to evaluate co-segregation of the variant with disease or to assign PP1 at any strength.
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength may increase with the number and informativeness of meioses.
No proband phenotype or phenotype-specificity evidence was provided for the exact variant, and no applicable MBD4 VCEP/gene-specific specification was retrieved.
Generic ACMG/AMP fallback: PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
No validated variant-specific functional assay demonstrating preserved normal function was identified for NM_001276270.2:c.-1G>A. The case bundle contains no appropriately controlled RNA, splicing, protein, enzymatic, cellular, or other functional experiment establishing a benign effect. Therefore BS3 cannot be assessed.
No unaffected relatives who were tested for the variant are identified, and no phenotype-defined non-segregation observations are available. BS4 cannot be assessed from the supplied evidence.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires informative family data and consideration of penetrance, phenocopies, and phenotype definition.
No applicable MBD4-specific VCEP or gene framework was available, so the generic ACMG/AMP BP2 concept was considered. The bundle contains no documented occurrence of this variant in trans with a pathogenic variant for a dominant condition or in cis with a pathogenic variant, and no phase or inheritance information to evaluate BP2. BP2 therefore cannot be assessed.
No case-level evidence shows that this variant was identified in an individual whose phenotype is fully explained by an alternative molecular diagnosis.
Generic ACMG/AMP fallback: BP5 requires observation in a case with an alternative molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001276270.2:c.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001276270.2:c.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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_missense
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.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). 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
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001276270.2:c.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001276270.2:c.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001276270.2:c.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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_missense
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.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). 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.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). 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)341 / 1,176,170 | 0.00029 |
| Remaining individuals13 / 62,166 | 0.00021 |
| Middle Eastern1 / 6,072 | 0.00016 |
| Admixed American7 / 59,678 | 0.00012 |
| Ashkenazi Jewish1 / 29,404 | 3.4e-05 |
| Remaining individuals2 / 6,874 | 0.00029 |
| European (non-Finnish)35 / 124,346 | 0.00028 |
| Admixed American3 / 34,694 | 8.6e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000225752; MAF= 0.02258%, 363/1607956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000289924; MAF= 0.02899%, 341/1176170 alleles, homozygotes = 0); grpmax FAF= 0.00026455.
This variant is present in gnomAD v2.1 (AF= 0.000146547; MAF= 0.01465%, 40/272950 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000290951; MAF= 0.02910%, 2/6874 alleles, homozygotes = 0); grpmax FAF= 0.00041979.
Not available in gnomAD-Canada v1.0.
BP4 is met at supporting strength. No MBD4 VCEP/CSPEC PP3/BP4 specification is available. This is a non-missense variant, so the generic splice-prediction path uses SpliceAI rather than REVEL. SpliceAI maximum delta is 0.00, below the <0.10 BP4 supporting threshold.
generic_spliceai: BP4_supporting if max_delta < 0.10
PP3 is not met. No MBD4 VCEP/CSPEC PP3/BP4 specification is available, so the generic splice-prediction path applies to this non-missense variant. SpliceAI maximum delta is 0.00, which does not exceed the >0.20 PP3 supporting threshold. PP3 is also not used to duplicate the splice-prediction evidence considered for the canonical-splice PVS1 assessment.
generic_spliceai: PP3_supporting if max_delta > 0.20; not met at 0.00; do not duplicate PVS1 splice-prediction evidence
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.-1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.(=). 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).
6 paper records listed. 1 cited in the classification. 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.
Location Proposed Criteria for Interpretation of Sequence Variants, introductory paragraphs
Context General ACMG/AMP expert-consensus guideline development; no MBD4-specific experiment, cohort, or variant-level functional result is described.
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= 0.000225752; MAF= 0.02258%, 363/1607956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000289924; MAF= 0.02899%, 341/1176170 alleles, homozygotes = 0); grpmax FAF= 0.00026455.
This variant is present in gnomAD v2.1 (AF= 0.000146547; MAF= 0.01465%, 40/272950 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000290951; MAF= 0.02910%, 2/6874 alleles, homozygotes = 0); grpmax FAF= 0.00041979.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3543760)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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).