Classification rationale

BP4 VUS

MBD4 c.-1G>A canonical_splice · exon 1

VUS: BP4 supporting because SpliceAI maximum delta score is 0.00, indicating no predicted splice impact.

BP4 → 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_001276270.2 · variants mapped to exon structure

MBD4 NM_001276270.2

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

BP4 supporting Benign

Met, supporting: SpliceAI maximum delta 0.00 meets the BP4 threshold of <=0.1 for no predicted splice impact.

Variant consequence: canonical_splice at NM_001276270.2:c.-1G>A in MBD4; protein consequence NP_001263199.1:p.(=).SpliceAI scores: DS_AG=0.00, DS_AL=0.00, DS_DG=0.00, DS_DL=0.00; maximum delta score=0.00.Published calibration: SpliceAI BP4 supporting requires <=0.1, based on Jaganathan et al. 2019 (PMID:30661751).

spliceai ↗

Assessed · not applied · 8 not met · 11 not assessed

Pathogenic

PVS1 Not met: c.-1G>A is a 5' UTR variant with predicted protein consequence p.(=) and SpliceAI maximum delta 0.00, not an established loss-of-function variant.

PS2 Not assessed: no documented proband with confirmed absence of the variant in both biological parents is available.

PS3 Not assessed: no validated variant-specific functional assay is documented; SpliceAI max delta 0.00 is computational prediction, not assay evidence.

PS4 Not assessed: no exact-variant case-control counts or enrichment statistic are available to evaluate PS4.

PM2 Not met: gnomAD v4.1 total allele frequency is 0.000225752, exceeding the generic PM2 threshold of 0.0001.

PM3 Not assessed: no affected proband, second pathogenic MBD4 variant, or phase information establishes this variant in trans with a disease-causing allele.

PM6 Not assessed: no publication or clinical record reports a presumed de novo occurrence without parental testing.

PP1 Not assessed: zero informative meioses or affected-relative segregation observations are documented for this variant.

PP3 Not met: SpliceAI maximum delta 0.00 is below the PP3 supporting threshold of >=0.2.

PP4 Not assessed: no patient phenotype or disease-specific clinical presentation is available to evaluate MBD4 phenotype specificity.

PP5 Not met: ClinVar has zero expert-panel submissions for the exact variant, and the two laboratory submissions are Uncertain significance.

Benign

BA1 Not met: gnomAD v4.1 total allele frequency is 0.000225752, far below the generic BA1 threshold of 0.05.

BS1 Not met: the highest gnomAD v4.1 population frequency is 0.000289924, below the generic BS1 threshold of 0.01.

BS2 Not met: gnomAD v4.1 reports 0 homozygotes, so no qualifying healthy-adult genotype is available for BS2.

BS3 Not assessed: no validated variant-specific functional assay is documented; SpliceAI max delta 0.00 cannot establish a normal functional effect.

BS4 Not assessed: no tested affected or unaffected relatives provide informative non-segregation evidence for this variant.

BP2 Not assessed: no phase-resolved observation shows this variant in trans or cis with a pathogenic allele in an informative individual.

BP5 Not assessed: no affected patient with a confirmed alternative molecular diagnosis is documented for BP5.

BP6 Not met: ClinVar has zero expert-panel submissions for the exact variant, and the two laboratory submissions are Uncertain significance.

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= 0.000225752; MAF= 0.02258%, 363/1607956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000289924; MAF= 0.02899%, 341/1176170 alleles, homozygotes = 0); grpmax FAF= 0.00026455.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000146547; MAF= 0.01465%, 40/272950 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000290951; MAF= 0.02910%, 2/6874 alleles, homozygotes = 0); grpmax FAF= 0.00041979.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.023% · 363 / 1,607,956
0 hom · FAF 0.026%

European (non-Finnish) 341 / 1,176,170	0.029%
Remaining individuals 13 / 62,166	0.021%
Middle Eastern 1 / 6,072	0.016%
Admixed American 7 / 59,678	0.012%
Ashkenazi Jewish 1 / 29,404	0.0034%

+ 5 not observed (European (Finnish), Amish, East Asian, South Asian, African/African American)

gnomAD v2.1

0.015% · 40 / 272,950
0 hom · FAF 0.042%

Remaining individuals 2 / 6,874	0.029%
European (non-Finnish) 35 / 124,346	0.028%
Admixed American 3 / 34,694	0.0086%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), 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 Uncertain significance (2 clinical laboratories). (ClinVarID = 3543760)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MBD4, a DNA glycosylase, is infrequently altered in cancer.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 6 PMIDs not cited in assessment

23652378 ↗ A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document. CLINVAR

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

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 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

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