NM_001276270.2:c.1375T>A

MBD4 · NP_001263199.1:p.(Phe459Ile) · NM_001276270.2

GRCh37: chr3:129152711 A>T · GRCh38: chr3:129433868 A>T

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Phe459Ile)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

PP3 supporting: REVEL 0.658 meets the calibrated missense threshold of at least 0.644.

Final determination: Under the generic ACMG/AMP 2015 fallback, PM2 supporting plus PP3 supporting provides two supporting criteria, which does not meet any definitive or likely classification combination and therefore results in VUS.

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	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.1375T>A in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Phe459Ile). 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.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic p.Phe459Ile comparator was identified, and ClinVar returned no record for c.1375T>A.	clinvar
PS2	Not assessed	Not assessed: no parental genotypes or confirmed absence of c.1375T>A in both parents are documented for de novo evaluation.
PS3	Not assessed	Not assessed: No variant-specific functional assay, validated controls, or quantitative activity result was available for MBD4 p.Phe459Ile.
PS4	Not assessed	Not assessed: no affected-carrier, control-comparison, or case-control enrichment data are available for this variant.
PM1	Not assessed	Not assessed: no authoritative MBD4 domain table covered residue F459, and the hotspot search returned no statistically significant hotspot.
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with allele frequency <=0.0001 for generic PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, second pathogenic allele, phase result, or inheritance data is available for MBD4 p.Phe459Ile.	generic_acmg_combination_rules
PM4	N/A	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.1375T>A in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Phe459Ile). 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.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: zero eligible pathogenic or likely pathogenic alternate missense comparators were identified at MBD4 residue 459.	pm5_candidates
PM6	Not assessed	Not assessed: no reported suspected de novo occurrence with phenotype and proband evidence is available when parental testing is absent.
PP1	Not assessed	Not assessed: no informative affected-relative segregation, unaffected-relative testing, meioses, or phenotype concordance is documented.
PP2	Not met	Not met: available MBD4 evidence supports loss of function, not the required predominantly missense disease mechanism with uncommon benign missense variation.	pvs1_gene_context
PP3	Met	Met, supporting: REVEL 0.658 meets the >=0.644 missense PP3 threshold calibrated by ClinGen SVI (PMID:36413997).	revel
PP4	Not assessed	Not assessed: no individual-level phenotype or highly specific clinical diagnosis is supplied for the variant carrier.
PP5	Not met	Not met: ClinVar reports no exact-variant result, so no expert-panel Pathogenic or Likely pathogenic assertion supports PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no observed allele frequency reaching the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows no variant observation, but provides no unaffected adult homozygote or healthy-carrier observation for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: No controlled functional assay demonstrated normal MBD4 activity for p.Phe459Ile.
BS4	Not assessed	Not assessed: no appropriately tested unaffected relatives carrying c.1375T>A or other informative non-segregation evidence is documented.
BP1	Not assessed	Not assessed: MBD4 loss-of-function evidence exists, but a primarily truncating disease variant spectrum has not been established.	pvs1_gene_context
BP2	Not assessed	Not assessed: no pathogenic comparator variant, cis/trans phase result, affected-status context, or inheritance data is available for MBD4 p.Phe459Ile.	generic_acmg_combination_rules
BP3	N/A	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.1375T>A in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Phe459Ile). 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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.658 exceeds the <=0.29 missense BP4 threshold calibrated by ClinGen SVI (PMID:36413997).	revel
BP5	Not assessed	Not assessed: no patient-level alternative molecular diagnosis is documented to explain the relevant phenotype.
BP6	Not met	Not met: ClinVar reports no exact-variant result, so no expert-panel Benign or Likely benign assertion supports BP6.	clinvar
BP7	N/A	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.1375T>A in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Phe459Ile). 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.	generic_acmg_combination_rules

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