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

VUS

PM2 supporting 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) in MBD4 is a missense variant with no ClinVar classification and no variant-specific functional data.

The variant is extremely rare in population databases (gnomAD v4.1: 1/1,593,284 alleles, AF = 6.28 × 10⁻⁷), satisfying PM2 at supporting strength.

Multiple concordant computational predictors (REVEL 0.016, BayesDel −0.65999, SpliceAI 0.00) predict a benign effect, satisfying BP4 at supporting_benign strength.

PM2 (supporting pathogenic) and BP4 (supporting benign) represent equal-weight opposing evidence; under generic ACMG/AMP 2015 rules (PMID:25741868), this results in a Variant of Uncertain Significance (VUS).

No variant-specific publications, functional studies, de novo reports, segregation data, or external classifications were identified to further inform interpretation.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The PVS1 variant assessment confirms no eligibility under the ClinGen SVI generic PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No evidence of a different nucleotide change at codon 30 resulting in the same amino acid change (Pro30Leu) classified as pathogenic in ClinVar or the literature.
PS2	Not assessed	No de novo reports with confirmed paternity and maternity identified for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data comparing affected individuals to controls available for this variant.
PS5	Not assessed	No alternative reputable source (ClinVar, VCEP, or clinical laboratory) has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
PM1	Not met	This variant (p.Pro30Leu) is not located in a statistically significant mutational hotspot. Cancer Hotspots analysis found no significant hotspot at residue Pro30. The residue is in the N-terminal region of MBD4, upstream of the methyl-CpG binding domain (residues ~82-147), and there is no evidence it lies within a critical, well-established functional domain.
PM2	Met	This variant is extremely rare in population databases. gnomAD v4.1 reports a single heterozygous allele among 1,593,284 total alleles (allele frequency = 6.28 × 10⁻⁷, or 0.000063%), which is well below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	Not assessed	No pathogenic missense variants identified at the same amino acid residue (Pro30) for comparison. PM5 candidate harvesting found no eligible comparators.	pm5_candidates
PM6	Not assessed	No assumed de novo reports without confirmation of paternity and maternity identified for this variant.
PP1	Not assessed	No co-segregation data available for this variant in affected families.
PP2	Not assessed	Insufficient data to assess whether MBD4 has a low rate of benign missense variation. No gene-level missense constraint metrics (Z-score, gnomAD missense o/e) are available in the evidence packet. HCI prior is not available for MBD4.
PP3	Not met	Multiple lines of computational evidence support a benign effect. REVEL score is 0.016 (well below the 0.5 threshold, predicting benign), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All available in silico predictors agree on a benign interpretation.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data specific to this case are available for review.
PP5	Not assessed	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	Allele frequency is far below the 1% BA1 threshold (non-VCEP). gnomAD v4.1 reports a single allele (AF = 6.28 × 10⁻⁷).	gnomad_v4
BS1	Not met	Allele frequency is far below the 0.3% BS1 threshold (non-VCEP). gnomAD v4.1 reports a single allele (AF = 6.28 × 10⁻⁷).	gnomad_v4
BS2	Not assessed	No data available regarding observation of this variant in healthy adults for a disorder with full penetrance expected at an early age.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant.
BS4	Not assessed	No non-segregation data available for this variant in affected families.
BP1	Not assessed	Although truncating MBD4 variants have been reported as pathogenic (e.g., c.217C>T/p.Gln73* in PMID:31322271), there is insufficient evidence that missense variants in MBD4 are not a disease mechanism. The gene-level evidence suggests a multi-tumor predisposition syndrome with LoF as a mechanism, but missense variants have not been systematically excluded.
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic variant (recessive disorders) or in cis with a pathogenic variant (any inheritance).
BP4	Met	Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.016 (strongly benign-predicting), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico tools concordantly predict a benign effect.	revel bayesdel spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in a case harboring this variant.
BP6	Not assessed	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	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 splice impact.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders; MBD4-associated disease (multi-tumor predisposition) is not established as a recessive condition, and no recessive context exists for this variant.
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants; this is a missense substitution.

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