Variant classification summary

NM_001276270.2:c.106A>G

MBD4 · NP_001263199.1:p.(Lys36Glu) · NM_001276270.2

GRCh37: chr3:129156792 T>C · GRCh38: chr3:129437949 T>C

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Lys36Glu)

gnomAD AF

5.6641677197822945e-06 (v4.1)

ClinVar

Conflicting classifications of pathogenicity

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001276270.2:c.106A>G (p.Lys36Glu) in MBD4 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1: 5/251,106 alleles, 0.0020%; v4.1: 9/1,588,936 alleles, 0.00057%), meeting PM2 at supporting strength.

2

Multiple in silico tools predict a benign effect: REVEL score 0.009, BayesDel score -0.666, and SpliceAI max delta 0.00, supporting BP4 (supporting benign).

3

No functional studies, segregation data, or case-control evidence specific to this variant were identified. ClinVar classifications are conflicting (2-star) and do not meet the 3-star expert panel threshold for PP5 or BP6.

4

The evidence profile consists of one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in insufficient evidence to classify this variant as either pathogenic or benign. This variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.

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	Variant is a missense substitution (c.106A>G, p.Lys36Glu) and does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant producing the same amino acid change (p.Lys36Glu) was identified in ClinVar or the literature. PS1 evidence is absent.	clinvar
PS2	N/A	No de novo occurrence data are available for this variant.
PS3	Not met	No functional experimental data were identified for this variant. OncoKB reports unknown oncogenic effect; no literature contains functional characterization of c.106A>G (p.Lys36Glu). Domain-level inference alone does not satisfy PS3.	oncokb
PS4	Not met	No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls.
PS5	N/A	PS5 is not a criterion defined in the standard ACMG/AMP 2015 framework used for this assessment.
PM1	Not met	Position 36 (p.Lys36Glu) is in the N-terminal region of MBD4 outside the methyl-CpG binding domain (MBD, residues ~82–147) and the DNA glycosylase domain. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. No literature establishes this N-terminal region as a critical functional domain.	pvs1_variant_assessment
PM2	Met	This variant is extremely rare in population databases: gnomAD v2.1 (5/251,106 alleles, AF=0.0020%), gnomAD v4.1 (9/1,588,936 alleles, AF=0.00057%). Combined AF ~0.00076%, well below the 0.1% threshold for PM2_supporting. No homozygotes observed.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants with established pathogenic classification were identified. PM5 candidate harvesting was unable to confirm classic same-residue semantics.	pm5_candidates
PM6	N/A	No de novo occurrence data or maternity/paternity confirmation reported for this variant.
PP1	N/A	No segregation data are available for this variant in affected families.
PP2	Not met	No gene-level missense constraint data (z-score) or evidence that MBD4 has a low rate of benign missense variation with pathogenic missense variants as a common mechanism was identified in the evidence brief.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.009 (benign-leaning, below 0.5 threshold), BayesDel score -0.666 (negative, benign-leaning), SpliceAI max delta 0.00 (no predicted splice impact). Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	N/A	No patient phenotype or clinical data specific to this variant were provided for assessment.
PP5	Not met	ClinVar review status for Variation ID 2904168 is 'criteria provided, conflicting classifications' (2 stars), which does not meet the 3-star expert panel threshold required for PP5_supporting. Two submitters report Likely benign (Ambry Genetics) and Uncertain significance (Invitae).	clinvar
BA1	Not met	Combined population frequency ~0.00076% is far below the 1% threshold for BA1. This variant is not common in the general population.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency ~0.0020% (v2.1) and ~0.00057% (v4.1) are both far below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	N/A	No data on observation of this variant in healthy adults with full penetrance expected at an early age were available.
BS3	Not met	No experimental functional studies demonstrating a benign effect for this variant were identified. In silico predictions (REVEL, BayesDel) are assessed under BP4, not BS3.
BS4	N/A	No segregation data are available for this variant.
BP1	Not met	MBD4 is a gene in which both truncating and missense germline variants have been associated with disease (MBD4 tumor predisposition syndrome; PMID:35460607). Truncating variants are not the sole disease mechanism, so BP1 does not apply.
BP2	N/A	No data on observation in trans with a known pathogenic MBD4 variant available.
BP4	Met	Multiple in silico computational tools predict a benign effect: REVEL score 0.009 (well below 0.5 threshold; PMID:36413997), BayesDel score -0.666 (negative, benign-leaning), and SpliceAI max delta 0.00 (no predicted splicing impact). The concordance of benign predictions from independent tools supports BP4_supporting.	revel bayesdel spliceai
BP5	N/A	No alternate molecular basis for disease was identified to explain the phenotype independent of this variant.
BP6	Not met	ClinVar review status is 'criteria provided, conflicting classifications' (2 stars), which does not meet the 3-star expert panel threshold for BP6_supporting. While Ambry Genetics classifies as Likely benign, the conflicting VUS classification and 2-star review status preclude BP6 application.	clinvar
BP7	N/A	This is a missense variant (c.106A>G, p.Lys36Glu) not a synonymous or intronic variant at a position where splicing is not predicted to be altered. BP7 applies only to synonymous variants.

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