Variant classification summary

NM_004656.4:c.67+5G>C

BAP1 · NP_004647.1:p.? · NM_004656.4

GRCh37: chr3:52443725 C>G · GRCh38: chr3:52409709 C>G

Gene: BAP1 Transcript: NM_004656.4

Final call

VUS

PM2 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.?

gnomAD AF

1.4869612088994628e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because gnomAD allele frequencies are below the <=0.0001 threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one supporting criterion alone does not meet any pathogenic, likely pathogenic, likely benign, or benign combination, resulting in VUS.

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 met	Not met: the intronic +5 variant has no established null consequence, and SpliceAI max delta is 0.161, below the 0.2 splice-impact threshold.	pvs1_generic_framework PMID:25741868 spliceai
PS1	N/A	Not applicable: c.67+5G>C is intronic and has no defined amino-acid consequence for same-codon comparison.
PS2	Not assessed	Not assessed: no proband-parent genotypes or confirmed parental testing are documented for this variant.
PS3	Not assessed	Not assessed: no variant-specific RNA or protein assay was reported, and SpliceAI max delta 0.161 is computational rather than functional evidence.	spliceai PMID:25741868 PMID:26467025
PS4	Not assessed	Not assessed: no exact-variant case-control dataset, affected-carrier count, control-carrier count, or enrichment statistic is available.
PM1	N/A	Not applicable: the intronic variant has no amino-acid residue, and no BAP1 authoritative domain table is available.
PM2	Met	Met at supporting strength: gnomAD v2.1 all-comers AF 1.99103e-05 is below the <=0.0001 PM2 Supporting threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: PM3 requires recessive biallelic or confirmed in-trans evidence, whereas BAP1 tumor predisposition is autosomal dominant.
PM4	N/A	Not applicable: this intronic variant has no established in-frame indel or demonstrated protein-length change; the protein consequence remains p.?.	pvs1_generic_framework
PM5	N/A	Not applicable: c.67+5G>C is intronic with protein consequence p.?, so no same-residue missense comparison exists.
PM6	Not assessed	Not assessed: no apparently de novo occurrence without parental testing is documented in an affected proband.
PP1	Not assessed	Not assessed: zero informative affected-relative transmissions or meioses are documented for this variant.
PP2	N/A	Not applicable: PP2 is a missense-gene-mechanism criterion, whereas this variant is intronic with p.? consequence.
PP3	Not met	Not met: SpliceAI maximum delta 0.161 is below the >=0.2 supporting PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no exact-variant carrier phenotype is documented, so phenotype specificity for BAP1-related disease cannot be evaluated.	clinvar
PP5	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the highest all-comers gnomAD allele frequency is 1.99103e-05, far below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest all-comers gnomAD allele frequency is 1.99103e-05, below the 0.01 generic BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no phenotype-confirmed healthy-carrier or penetrance evidence required for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign RNA or protein assay was reported, and SpliceAI max delta 0.161 cannot demonstrate normal BAP1 function.	spliceai PMID:25741868 PMID:26467025
BS4	Not assessed	Not assessed: no informative non-segregation observation, such as an affected relative lacking the variant, is documented.
BP1	N/A	Not applicable: BP1 is restricted to missense variants, while c.67+5G>C is intronic with no defined protein change.
BP2	Not assessed	Not assessed: no confirmed cis phase or affected-proband co-occurrence with a pathogenic BAP1 variant is reported for c.67+5G>C.	clinvar
BP3	N/A	Not applicable: c.67+5G>C is an intronic single-nucleotide substitution, not an in-frame indel in a repetitive protein region.
BP4	Not met	Not met: SpliceAI maximum delta 0.161 exceeds the <=0.1 supporting BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no affected exact-variant carrier with an alternative molecular diagnosis is documented for BP5 evaluation.	clinvar
BP6	Not met	Not met: the exact ClinVar record has 0 expert-panel submissions, so laboratory Likely benign assertions cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: the variant is intronic, not synonymous, so BP7 is out of scope.

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.