Variant classification summary

NM_001276270.2:c.1684G>C

MBD4 · NP_001263199.1:p.(Asp562His) · NM_001276270.2

GRCh37: chr3:129150385 C>G · GRCh38: chr3:129431542 C>G

Gene: MBD4 Transcript: NM_001276270.2

Final call

Likely Benign

BS1 strong BP4 moderate BP1 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Asp562His)

gnomAD AF

0.007183541086532286 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 (strong) - gnomAD v4.1 grpmax filtering AF 1.047% (South Asian 1.104%) exceeds the 1% threshold, with 71 homozygotes reported.

2

Likely Benign: BP4 (moderate) - REVEL 0.178 falls in the benign band (at or below 0.183) for this missense change.

3

Likely Benign: BP1 (supporting) - missense variant in MBD4, a gene in which disease is caused primarily by truncating loss-of-function variants.

4

Likely Benign: combination - one strong benign (BS1) plus one supporting benign (BP1) criterion; no pathogenic criterion met and BA1 not met, so the call is Likely Benign rather than Benign.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion (BS1) plus one supporting benign criterion (BP1) - alternatively two benign criteria counting BP4 at moderate - yields Likely Benign.

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.1684G>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Asp562His). 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 met	Not met: no MBD4 variant with a different nucleotide change encodes p.(Asp562His), and this amino acid change has no established pathogenic classification in ClinVar.	clinvar
PS2	Not assessed	Not assessed: no proband or parental-testing data exist, and the variant is common in gnomAD (v4.1 AF 0.72%, 71 homozygotes), so a confirmed de novo occurrence is unsupported.	PMID:25741868 final_classification_framework clinvar gnomad_v2 gnomad_v4 gnomad_canada
PS3	Not assessed	Not assessed: no functional assay for MBD4 p.(Asp562His) was found in ClinVar, OncoKB, COSMIC or the literature, so the PS3 assay requirement is unmet.	clinvar oncokb PMID:25741868
PS4	Not met	Not met: no case-control enrichment study exists for c.1684G>C, and gnomAD v2.1 AF 0.005111 (1444 alleles, 12 homozygotes) is inconsistent with case enrichment.	clinvar gnomad_v2 PMID:23169492 PMID:24121147 PMID:25741868
PM1	Not met	Not met: CancerHotspots reports no significant hotspot at D562 and the codon carries benign variation, including 12 gnomAD v2.1 homozygotes at 0.51% allele frequency.	clinvar gnomad_v2
PM2	Not met	Not met: gnomAD v4.1 all-comers AF 0.718% (11,588 alleles) far exceeds the 0.0001 PM2 supporting threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	Not met	Not met: no pathogenic MBD4 variant in trans with c.1684G>C, and gnomAD v4.1 shows 71 homozygotes (AF 0.72%) at this allele.	PMID:25741868 pvs1_gene_context clinvar gnomad_v2 gnomad_v4
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.1684G>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Asp562His). 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 met	Not met: no missense variant introducing a different amino acid at codon 562 is established pathogenic - the only other ClinVar codon-562 entry is a benign synonymous change.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no submission or publication reports this variant as de novo, and gnomAD v4.1 lists 71 homozygotes, arguing against a rare de novo allele.	PMID:25741868 final_classification_framework clinvar gnomad_v2 gnomad_v4
PP1	Not assessed	Not assessed: no affected family members were genotyped, so co-segregation with disease cannot be evaluated for this variant.	PMID:25741868 final_classification_framework clinvar pvs1_gene_context
PP2	Not met	Not met: MBD4-associated disease is attributable to loss-of-function variants rather than missense, and no gene-level missense-constraint metric is available to satisfy PP2.	clinvar pvs1_gene_context PMID:25741868
PP3	Not met	Not met: REVEL 0.178 is below the 0.644 supporting threshold for PP3 in this missense variant.	revel
PP4	Not assessed	Not assessed: no proband phenotype or HPO terms were provided, and the only available labels ('Inborn genetic diseases', 'not specified') carry no specificity.	clinvar PMID:25741868
PP5	Not met	Not met: ClinVar variation 218624 has zero expert-panel submissions, all seven being single-submitter clinical laboratories with conflicting classifications (1-star review status).	clinvar PMID:25741868 PMID:23169492 PMID:24121147
BA1	Not met	Not met: the highest credible population frequency is 3.07% (gnomAD v4.1 Amish), below the 5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS1	Met	Met at strong: gnomAD v4.1 grpmax filtering AF of 1.047% exceeds the 1% BS1 threshold (South Asian AF 1.10%).	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS2	Not met	Not met: 71 gnomAD v4.1 homozygotes exist, but BS2 requires a fully penetrant early-onset disorder and MBD4 predisposition is adult-onset.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS3	Not assessed	Not assessed: no functional assay showing normal/benign MBD4 p.(Asp562His) function was found in any consulted source, so BS3's assay requirement is unmet.	clinvar oncokb PMID:25741868
BS4	Not assessed	Not assessed: no family genotypes are available, and the only ClinVar mention of non-segregation is a templated comment, not a segregation observation.	PMID:25741868 final_classification_framework clinvar
BP1	Met	Met at supporting strength: MBD4-associated disease is caused primarily by truncating loss-of-function variants, and no MBD4 missense variant has reached established pathogenic status.	clinvar pvs1_gene_context PMID:25741868
BP2	Not met	Not met: no cis/trans phase with a pathogenic MBD4 variant, and MBD4 predisposition is bi-allelic recessive (Palles et al. 2022, PMID:35460607), not dominant.	PMID:25741868 pvs1_gene_context clinvar gnomad_v2 gnomad_v4
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.1684G>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Asp562His). 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 at moderate strength: REVEL 0.178 is at or below the 0.183 moderate BP4 threshold for this missense variant.	revel
BP5	Not assessed	Not assessed: no proband genotype or co-occurring variant information is available to determine whether an alternate molecular basis explains the phenotype.	clinvar PMID:25741868
BP6	Not met	Not met: the benign-leaning ClinVar majority comes from single-submitter clinical laboratories with zero expert-panel submissions, which BP6 does not accept.	clinvar PMID:25741868
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.1684G>C in MBD4 is a missense substitution predicted to produce NP_001263199.1:p.(Asp562His). 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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