NM_003925.3:c.1177T>G

MBD4 · NP_003916.1:p.(Phe393Val) · NM_003925.3

GRCh37: chr3:129155310 A>C · GRCh38: chr3:129436467 A>C

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.(Phe393Val)

gnomAD AF

6.1960479127993e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_003925.3:c.1177T>G (p.Phe393Val) in MBD4 is a rare missense variant absent from gnomAD v2.1 and observed as a single heterozygous allele in gnomAD v4.1 (1/1,613,932; AF=0.000062%), meeting PM2 at supporting level.

Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.174 (tolerated), BayesDel score −0.216 (benign), and SpliceAI max delta 0.00 (no splicing impact), meeting BP4 at supporting benign level.

MBD4-associated disease is driven primarily by loss-of-function (truncating) variants. This missense variant occurs in a gene for which the predominant pathogenic mechanism is truncation, meeting BP1 at supporting benign level.

Two clinically validated in silico prediction algorithms (BayesDel, REVEL) plus a splicing predictor (SpliceAI) all return results inconsistent with pathogenicity, further supporting BP4.

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.1177T>G (p.Phe393Val) is a missense variant; it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No alternative pathogenic missense change at the same amino acid residue (Phe393) has been identified in ClinVar to support PS1 (same residue, different pathogenic change).	clinvar
PS2	Not met	No confirmed de novo occurrence data are available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies supportive of a damaging effect have been identified for this variant.	oncokb
PS4	Not met	The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls.
PS5	N/A	PS5 is not a criterion in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868); no CSPEC/VCEP framework defines a PS5 rule for MBD4.	generic_acmg_combination_rules
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot and is not located in a well-established critical functional domain where benign variation is absent.
PM2	Met	This variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (1/1,613,932 alleles; 0.000062%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No alternative pathogenic missense variant at the same amino acid residue (Phe393) was identified in ClinVar; PM5 requires a different pathogenic change at the same residue.	pm5_candidates
PM6	Not met	No confirmed de novo occurrence has been reported for this variant, with or without parental confirmation.
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	Not met	MBD4-associated disease is primarily driven by loss-of-function (truncating) variants; there is insufficient evidence that missense variants are a common disease mechanism or that the gene has a low rate of benign missense variation, as required for PP2.	pvs1_gene_context
PP3	Not met	Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.174 (below the 0.5 damaging threshold), BayesDel score −0.216 (benign range), and SpliceAI max delta 0.00 (no predicted splicing impact). PP3 requires multiple lines of computational evidence supporting a deleterious effect, which is not met here.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or detailed clinical information is available to assess whether this variant segregates with a disease presentation specific for MBD4.
PP5	Not met	No reputable source (expert panel or clinical laboratory with strong internal validation) has classified this variant as pathogenic. ClinVar records show only VUS classifications from two clinical laboratories.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), well below the 1% BA1 stand-alone benign threshold.	gnomad_v4
BS1	Not met	Allele frequency in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), well below the 0.3% BS1 threshold for a variant being too common to cause a highly penetrant disorder.	gnomad_v4
BS2	Not met	The single heterozygous observation in gnomAD v4.1 is insufficient to meet BS2 (observed in a healthy adult with full penetrance expected at an early age) without specific clinical confirmation that the individual was unaffected at an advanced age, especially given the variable penetrance of MBD4-associated cancer predisposition.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant.	oncokb
BS4	Not met	No evidence of non-segregation with disease has been reported for this variant in affected families.
BP1	Met	MBD4-associated disease is primarily caused by loss-of-function (truncating) variants, as supported by published germline cases (e.g., c.217C>T/p.Gln73*). This missense variant occurs in a gene where the predominant pathogenic mechanism is truncation, satisfying BP1.	pvs1_gene_context
BP2	Not met	No evidence of this variant occurring in trans with a known pathogenic MBD4 variant has been reported; there is no observation in an autosomal recessive context.
BP4	Met	Multiple lines of computational evidence predict no deleterious impact: REVEL score 0.174 (tolerated, below the 0.5 damaging threshold), BayesDel score −0.216 (predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). This satisfies BP4 (supporting benign) with multiple concordant benign predictions.	revel bayesdel spliceai
BP5	Not met	No case has been identified in which this variant was found in a patient with an alternative molecular basis for disease that would explain the phenotype independently.
BP6	Not met	No reputable source has classified this variant as benign. ClinVar records show only Uncertain Significance classifications from two clinical laboratories.	clinvar
BP7	N/A	BP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus nor creation of a new splice site, and the nucleotide is not highly conserved. This is a missense variant, not a synonymous variant.

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