Variant classification summary

NM_001276270.2:c.1074C>T

MBD4 · NP_001263199.1:p.(Ile358=) · NM_001276270.2

GRCh37: chr3:129155413 G>A · GRCh38: chr3:129436570 G>A

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

BP7 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Ile358=)

gnomAD AF

0.00011461779611662516 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP7 supporting: synonymous variant with SpliceAI max delta 0.033, below the <=0.1 no-impact threshold.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting benign criterion alone does not meet Benign or Likely Benign thresholds, so the final call is 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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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	N/A	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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband genotype with confirmed absence of NM_001276270.2:c.1074C>T in both biological parents.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay with appropriate controls is reported for synonymous MBD4 c.1074C>T (p.Ile358=).
PS4	Not assessed	Not assessed: no variant-specific affected-case count, control comparison, or enrichment statistic is available for PS4.
PM1	N/A	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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 all-comers AF 0.000114618 exceeds the supplied PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected proband, second pathogenic MBD4 allele, or confirmed trans phase is documented for this synonymous variant.
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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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	N/A	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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no compatible proband case or presumed de novo occurrence without parental testing is documented for this variant.
PP1	Not assessed	Not assessed: no affected variant-positive relatives, informative meioses, or segregation series are documented for this variant.
PP2	N/A	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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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.	generic_acmg_combination_rules
PP3	Not met	Not met: synonymous-variant SpliceAI max delta 0.033 is below the >=0.2 PP3 supporting threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype, family history, or disease-specific clinical match is available for this exact variant.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions, and its exact-variant laboratory classifications are Benign or Likely benign.	clinvar
BA1	Not met	Not met: gnomAD v4.1 all-comers AF 0.000114618 is far below the supplied BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed gnomAD ancestry-specific AF is 0.00200337, below the supplied BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports zero homozygotes, with no qualifying healthy individual observed in the genotype context required for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no controlled variant-specific assay demonstrates normal MBD4 function for c.1074C>T (p.Ile358=) or provides a benign-effect threshold.
BS4	Not assessed	Not assessed: no clinically evaluated unaffected relatives with confirmed variant carriage are documented for this variant.
BP1	N/A	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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no affected individual has documented cis or trans phase with a pathogenic or benign MBD4 allele for this variant.
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.1074C>T in MBD4 is a synonymous (silent) substitution predicted to produce NP_001263199.1:p.(Ile358=). 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: SpliceAI max delta 0.033 meets <=0.1, but the same prediction is allocated to BP7 and cannot be double-counted for BP4.	spliceai
BP5	Not assessed	Not assessed: no affected case with a confirmed alternate molecular basis is documented for this exact variant.
BP6	Not met	Not met: ClinVar has zero expert-panel submissions, so its exact-variant laboratory Benign or Likely benign labels cannot trigger BP6.	clinvar
BP7	Met	Met, supporting: synonymous variant with SpliceAI max delta 0.033, below the <=0.1 no-impact threshold.	spliceai

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