Variant classification summary

NM_003925.3:c.1231_1234del

MBD4 · NP_003916.1:p.(Arg411GlyfsTer79) · NM_003925.3

GRCh37: chr3:129152946 CTTCT>C · GRCh38: chr3:129434103 CTTCT>C

Gene: MBD4 Transcript: NM_003925.3

Final call

VUS

PM2 supporting

Variant details

Gene

MBD4

Transcript

NM_003925.3

Protein

NP_003916.1:p.(Arg411GlyfsTer79)

gnomAD AF

1.2392541177316198e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD allele frequency 0.00124-0.00159%, far below the 0.1% threshold, with zero homozygotes.

2

Overall: VUS — the single supporting criterion (PM2) does not meet any ACMG/AMP 2015 Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold.

Final determination: Generic ACMG/AMP 2015 fallback (Richards et al. 2015, PMID:25741868): with only PM2 applied at supporting strength (1 supporting criterion), no pathogenic, likely pathogenic, benign, or likely benign combination threshold is satisfied, 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	Not assessed	Insufficient evidence was available to assess PVS1 (loss-of-function mechanism).
PS1	N/A	Not applicable: as a frameshift, no altered amino acid exists to compare with a previously established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband, family-history, or parental-testing data were available to evaluate a de novo occurrence.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no validated functional assay of this exact variant was available; functional data concern other MBD4 truncations only.	PMID:17285135 PMID:30049810 PMID:10545939 PMID:35460607 PMID:10637515
PS4	Not met	Not met: no case-control or prevalence study reports this exact variant, and gene-level disease association does not qualify.	PMID:30049810 PMID:35460607 gnomad_v4 generic_acmg_combination_rules
PM1	N/A	Not applicable: PM1 requires a missense change, but this frameshift leaves no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD allele frequency 0.00124-0.00159% is far below the 0.1% threshold, with zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada PMID:35460607
PM3	Not met	Not met: no source documents this variant in trans with a pathogenic variant, and no homozygotes are observed.	generic_acmg_combination_rules clinvar PMID:35460607 PMID:30049810 gnomad_v2 gnomad_v4
PM4	N/A	Not applicable: PM4 concerns in-frame length changes; a frameshift produces no protein length change to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this position to compare with a previously pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of this variant is documented, and no proband data exist to assess one.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family segregation data exist for this variant; segregation of other MBD4 alleles does not apply.	generic_acmg_combination_rules
PP2	N/A	Not applicable: PP2 applies to missense variants, and no missense change is present to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.06 is below the 0.2 splice-disruption threshold, and missense scores do not apply to a frameshift.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history information was available to judge phenotype specificity.	PMID:35460607 generic_acmg_combination_rules
PP5	Not met	Not met: no ClinGen expert-panel classification exists; three clinical-laboratory Pathogenic submissions do not trigger PP5.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: the highest allele frequency, 0.0174%, is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the highest allele frequency, 0.0174%, is about 17-fold below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 PMID:35460607 generic_acmg_combination_rules
BS2	Not met	Not met: zero homozygotes are observed in gnomAD v2.1 and v4.1, covering over 930,000 individuals.	gnomad_v2 gnomad_v4 PMID:35460607
BS3	Not met	Not met: no functional study shows preserved function, and all evidence points to loss of the glycosylase catalytic domain.	oncokb
BS4	Not assessed	Not assessed: no family testing data exist to demonstrate non-segregation with disease.	generic_acmg_combination_rules
BP1	N/A	Not applicable: BP1 applies to missense variants, and no missense change is present to evaluate.	generic_acmg_combination_rules
BP2	Not met	Not met: MBD4 deficiency is recessive, and no source reports this variant in cis with a pathogenic variant.	generic_acmg_combination_rules clinvar PMID:35460607 PMID:30049810
BP3	N/A	Not applicable: BP3 concerns in-frame indels in repetitive regions, and this variant is a frameshift.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the frameshift definitively alters the protein regardless of the low SpliceAI score (max delta 0.06).	spliceai generic_acmg_combination_rules
BP5	Not met	Not met: no alternative molecular cause is documented in the available clinical information.	generic_acmg_combination_rules
BP6	Not met	Not met: no expert-panel benign classification exists; ClinVar submissions classify the variant Pathogenic.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this frameshift alters the encoded protein.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.