Classification rationale

PM2 VUS

MBD4 c.1231_1234del frameshift

PM2 (Supporting): gnomAD allele frequency 0.00124-0.00159%, far below the 0.1% threshold, with zero homozygotes. Overall: VUS — the single supporting criterion (PM2) does not meet any ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold.

PM2 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_003925.3 · variants mapped to exon structure

MBD4 NM_003925.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met (supporting): gnomAD allele frequency 0.00124-0.00159% is far below the 0.1% threshold, with zero homozygotes.

gnomAD v2.1: AF 1.59093e-05 (0.00159%, 4/251426), 0 homozygotes, grpmax FAF 7.01e-06gnomAD v4.1: AF 1.23925e-05 (0.00124%, 20/1613874), 0 homozygotes, joint grpmax FAF 9.53e-06gnomAD v4.1 highest subpopulation FIN AF 1.56235e-05; gnomAD v2.1 highest subpopulation NFE_SEU AF 1.73883e-04 (0.0174%)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:35460607 ↗

Assessed · not applied · 12 not met · 7 not assessed

Pathogenic

PVS1 Insufficient evidence was available to assess PVS1 (loss-of-function mechanism).

PS2 Not assessed: no proband, family-history, or parental-testing data were available to evaluate a de novo occurrence.

PS3 Not assessed: no validated functional assay of this exact variant was available; functional data concern other MBD4 truncations only.

PS4 Not met: no case-control or prevalence study reports this exact variant, and gene-level disease association does not qualify.

PM3 Not met: no source documents this variant in trans with a pathogenic variant, and no homozygotes are observed.

PM6 Not assessed: no de novo occurrence of this variant is documented, and no proband data exist to assess one.

PP1 Not assessed: no family segregation data exist for this variant; segregation of other MBD4 alleles does not apply.

PP3 Not met: SpliceAI max delta 0.06 is below the 0.2 splice-disruption threshold, and missense scores do not apply to a frameshift.

PP4 Not assessed: no proband phenotype or family-history information was available to judge phenotype specificity.

PP5 Not met: no ClinGen expert-panel classification exists; three clinical-laboratory Pathogenic submissions do not trigger PP5.

Benign

BA1 Not met: the highest allele frequency, 0.0174%, is far below the 1% BA1 threshold.

BS1 Not met: the highest allele frequency, 0.0174%, is about 17-fold below the 0.3% BS1 threshold.

BS2 Not met: zero homozygotes are observed in gnomAD v2.1 and v4.1, covering over 930,000 individuals.

BS3 Not met: no functional study shows preserved function, and all evidence points to loss of the glycosylase catalytic domain.

BS4 Not assessed: no family testing data exist to demonstrate non-segregation with disease.

BP2 Not met: MBD4 deficiency is recessive, and no source reports this variant in cis with a pathogenic variant.

BP4 Not met: the frameshift definitively alters the protein regardless of the low SpliceAI score (max delta 0.06).

BP5 Not met: no alternative molecular cause is documented in the available clinical information.

BP6 Not met: no expert-panel benign classification exists; ClinVar submissions classify the variant Pathogenic.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23925e-05; MAF= 0.00124%, 20/1613874 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 1.56235e-05; MAF= 0.00156%, 1/64006 alleles, homozygotes = 0); grpmax FAF= 9.53e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.59093e-05; MAF= 0.00159%, 4/251426 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.62193e-05; MAF= 0.00462%, 1/21636 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0012% · 20 / 1,613,874
0 hom · FAF 0.00095%

European (Finnish) 1 / 64,006	0.0016%
European (non-Finnish) 18 / 1,179,940	0.0015%
South Asian 1 / 91,086	0.0011%

+ 7 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0016% · 4 / 251,426
0 hom · FAF 0.0007%

European (Finnish) 1 / 21,636	0.0046%
European (non-Finnish) 3 / 113,730	0.0026%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 1976297)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

35460607 ↗ Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

10545939 ↗ The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability. ONCOKB

10637515 ↗ Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency. ONCOKB

17285135 ↗ A human cancer-associated truncation of MBD4 causes dominant negative impairment of DNA repair in colon cancer cells. ONCOKB

25626707 ↗ Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. CLINVAR

30049810 ↗ MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. CLINVAR

22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

23881473 ↗ Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR

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