Variant classification summary

NM_001276270.2:c.-1G>A

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

GRCh37: chr3:129158677 C>T · GRCh38: chr3:129439834 C>T

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

BP4 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(=)

gnomAD AF

0.00022575244596245172 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 supporting because SpliceAI maximum delta score is 0.00, indicating no predicted splice impact.

Final determination: Under the generic ACMG/AMP 2015 fallback, a single supporting benign criterion does not meet the Benign or Likely Benign combinations, 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	Not met	Not met: c.-1G>A is a 5' UTR variant with predicted protein consequence p.(=) and SpliceAI maximum delta 0.00, not an established loss-of-function variant.	pvs1_generic_framework pvs1_variant_assessment spliceai
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.-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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented proband with confirmed absence of the variant in both biological parents is available.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay is documented; SpliceAI max delta 0.00 is computational prediction, not assay evidence.
PS4	Not assessed	Not assessed: no exact-variant case-control counts or enrichment statistic are available to evaluate 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.-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.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 total allele frequency is 0.000225752, exceeding the generic PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: no affected proband, second pathogenic MBD4 variant, or phase information establishes this variant in trans with a disease-causing allele.
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.-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.	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.-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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no publication or clinical record reports a presumed de novo occurrence without parental testing.
PP1	Not assessed	Not assessed: zero informative meioses or affected-relative segregation observations 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.-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.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.00 is below the PP3 supporting threshold of >=0.2.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical presentation is available to evaluate MBD4 phenotype specificity.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, and the two laboratory submissions are Uncertain significance.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total allele frequency is 0.000225752, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest gnomAD v4.1 population frequency is 0.000289924, below the generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, so no qualifying healthy-adult genotype is available for BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated variant-specific functional assay is documented; SpliceAI max delta 0.00 cannot establish a normal functional effect.
BS4	Not assessed	Not assessed: no tested affected or unaffected relatives provide informative non-segregation evidence 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.-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.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic allele in an informative individual.
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.-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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: SpliceAI maximum delta 0.00 meets the BP4 threshold of <=0.1 for no predicted splice impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected patient with a confirmed alternative molecular diagnosis is documented for BP5.
BP6	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, and the two laboratory submissions are Uncertain significance.	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.-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.	generic_acmg_combination_rules

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