NM_003925.3:c.89C>T

MBD4 · NP_003916.1:p.(Pro30Leu) · NM_003925.3

GRCh37: chr3:129158588 G>A · GRCh38: chr3:129439745 G>A

Gene: MBD4 Transcript: NM_003925.3

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

MBD4

Transcript

NM_003925.3

Protein

NP_003916.1:p.(Pro30Leu)

gnomAD AF

6.276344957961042e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_003925.3:c.89C>T (p.Pro30Leu) is a missense variant in MBD4, a gene in which germline loss-of-function variants cause a multi-tumor predisposition syndrome.

This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and observed at an allele frequency of 6.28e-07 (1/1,593,284 alleles) in gnomAD v4.1, meeting PM2 at supporting strength.

MBD4 germline disease is driven by loss-of-function via truncating variants; missense variants in this gene context meet BP1 at supporting benign strength.

Multiple orthogonal in silico predictors concordantly predict a benign effect: REVEL score 0.016, BayesDel score -0.660, and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.

Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): two supporting benign criteria (BP1, BP4) are met versus one supporting pathogenic criterion (PM2). The weight of evidence favors a likely benign classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	NM_003925.3:c.89C>T is a missense variant (p.Pro30Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). The generic PVS1 framework was explicitly deemed not applicable by the variant assessment scaffold.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant with the same amino acid change (Pro30Leu) via a different nucleotide substitution has been identified in ClinVar or the literature. PM5 candidate harvesting confirmed no same-residue comparator variants exist.	pm5_candidates clinvar
PS2	Not assessed	No de novo occurrence data are available for this variant. No publications or clinical reports document de novo inheritance with confirmed maternity and paternity.
PS3	Not assessed	No variant-specific functional data are available. OncoKB reports unknown oncogenic effect with no reviewed functional evidence for P30L. No publications with functional characterization of NM_003925.3:c.89C>T were identified.	oncokb
PS4	Not assessed	No case-control or cohort studies comparing variant prevalence in affected versus unaffected individuals are available. The variant is absent from ClinVar and has no associated case data.	clinvar
PS5	Not assessed	No reports of this variant occurring in multiple unrelated affected individuals are available. The variant is absent from ClinVar and has no literature reports.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot as determined by CancerHotspots.org analysis for MBD4 residue Pro30. No evidence of location within a well-established critical functional domain specifically linked to germline MBD4 pathogenicity.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present at an exceedingly low allele frequency of 6.28e-07 (1/1,593,284 alleles, no homozygotes) in gnomAD v4.1, well below the non-VCEP PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variants at the same amino acid residue (Pro30) were identified by PM5 candidate harvesting in ClinVar. No comparator variants exist at this residue to support PM5 application.	pm5_candidates
PM6	Not assessed	No de novo occurrence data with unconfirmed or confirmed parentage are available for this variant. PM6 requires a specific de novo report, which has not been identified.
PP1	Not assessed	No co-segregation data are available for this variant. No family studies or pedigrees with this variant have been reported.
PP2	Not met	MBD4 lacks evidence of a low rate of benign missense variation sufficient to meet PP2. No gene-level missense constraint metric (e.g., missense Z-score, gnomAD constraint) was retrieved to support this criterion. The established disease mechanism for MBD4 is loss-of-function via truncating variants, not missense clustering.	pvs1_gene_context
PP3	Not met	Multiple in silico tools predict a benign effect. REVEL score is 0.016 (strongly benign-leaning; well below 0.5 threshold). BayesDel score is -0.660 (strongly benign-leaning; negative scores favor benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No individual patient phenotype data are available for this variant. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease, which cannot be evaluated without clinical data.
PP5	Not assessed	This variant is absent from ClinVar and has not been classified as pathogenic by any reputable clinical laboratory or expert panel. No source to support PP5 was identified.	clinvar
BA1	Not met	The variant allele frequency is 6.28e-07 (0.00006%) in gnomAD v4.1, far below the BA1 threshold of >5% population frequency.	gnomad_v4
BS1	Not met	The variant allele frequency of 6.28e-07 (0.00006%) in gnomAD v4.1 is far below the non-VCEP BS1 threshold of >0.3% for a disorder expected to be rare. This frequency is not greater than expected for the disorder.	gnomad_v4
BS2	Not met	A single heterozygous observation (1/1,593,284 alleles, no homozygotes) in a population database does not meet the BS2 threshold for observation in healthy adults. BS2 requires either multiple observations in the homozygous state, or observation in trans with a pathogenic variant, or high frequency in controls for a fully penetrant dominant disorder. One allele in a general population database is insufficient.	gnomad_v4
BS3	Not assessed	No variant-specific functional studies demonstrating a benign effect are available. OncoKB shows unknown oncogenic effect with no reviewed functional data. No publications with functional characterization of this variant were identified.	oncokb
BS4	Not assessed	No family segregation data are available to assess lack of co-segregation with disease. No affected pedigrees with this variant have been reported.
BP1	Met	MBD4-related germline disease is established to be caused by loss-of-function (truncating) variants. The literature identifies nonsense and frameshift variants as the pathogenic mechanism (e.g., c.217C>T/p.Gln73* in PMID:31322271; multi-tumor predisposition from germline MBD4 deficiency in PMID:35460607). This missense variant is therefore in a gene where truncating variants are the primary known disease mechanism, consistent with BP1.	pvs1_gene_context
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic MBD4 variant. No phase information or compound heterozygote data exist.
BP4	Met	Multiple lines of computational evidence support a benign interpretation. REVEL score is 0.016 (strongly benign-leaning). BayesDel score is -0.660 (negative scores predict benign). SpliceAI delta score is 0.00 (no predicted splicing impact). These results from orthogonal in silico predictors are concordant in predicting no deleterious effect.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternative molecular basis for disease in an individual harboring this variant. No case-level clinical data exist for this variant.
BP6	Not assessed	This variant is absent from ClinVar and has not been classified as benign by any reputable clinical laboratory. No source to support BP6 was identified.	clinvar
BP7	N/A	NM_003925.3:c.89C>T is a missense variant (p.Pro30Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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