LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-10
Case ID: NM_144997.7_c.1177-5_1177-3del_20260810_203729
Framework: ACMG/AMP 2015
Variant classification summary

NM_144997.7:c.1177-5_1177-3del

FLCN  · NP_659434.2:p.?  · NM_144997.7
GRCh37: chr17:17119819 TGAG>T  ·  GRCh38: chr17:17216505 TGAG>T
Gene: FLCN Transcript: NM_144997.7
Final call
Pathogenic
PVS1 very strong PS3 strong PM2 moderate PP1 supporting PP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
FLCN
Transcript
NM_144997.7
Protein
NP_659434.2:p.?
gnomAD AF
4.337776455788763e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 (Very Strong): intronic deletion shown by minigene assay to cause out-of-frame exon 11 skipping, predicted to trigger nonsense-mediated decay.
2
PS3 (Strong): two independent validated minigene assays confirm complete exon 11 skipping and loss of the full-length FLCN protein.
3
PM2 (Moderate): maximum population allele frequency 0.00468%, far below the 0.1% threshold for this rare dominant disorder.
4
PP1 (Supporting): variant co-segregates with Birt-Hogg-Dubé syndrome in multiple affected family members across at least two families.
5
PP4 (Supporting): carriers consistently present the highly specific BHD phenotype (fibrofolliculomas, lung cysts/pneumothorax, chromophobe renal cell carcinoma).
6
Overall: Pathogenic — (1 PVS1) + (1 PS3) meets Pathogenic; independently, (1 PVS1) + (1 PM2) + (2 PP) also meets Pathogenic.
Final determination: Generic ACMG/AMP 2015 combination rules: (1 PVS1 very strong) + (1 PS strong) = Pathogenic, and additionally (1 PVS1) + (1 PM moderate) + (2 PP supporting) = Pathogenic; the adjudicated criteria set (PVS1 very strong, PS3 strong, PM2 moderate, PP1 supporting, PP4 supporting) satisfies both mappings, yielding Pathogenic.
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 Met Met (Very Strong): out-of-frame skipping of exon 11 (124 bp) experimentally confirmed by minigene assay, producing a premature stop codon expected to trigger nonsense-mediated decay.
pvs1_generic_framework pvs1_gene_context PMID:27734835 clinvar spliceai
PS1 N/A Not applicable: intronic deletion with no amino acid change (p.?), so no protein change exists to compare with a known pathogenic variant.
PMID:25741868 PMID:27734835
PS2 Not assessed Not assessed: no parental testing or de novo occurrence of this variant was reported in any proband.
PMID:25741868
PS3 Met Met (Strong): two independent validated minigene assays (PMID 28499369, 27734835) showed complete exon 11 skipping with loss of the full-length FLCN transcript.
PMID:28499369 PMID:27734835 PMID:25741868 pvs1_gene_context
PS4 Not met Not met: only case-level observations across multiple affected families exist; no formal case-control study with statistical support was performed.
PMID:27734835 PMID:28499369 PMID:19802896 clinvar gnomad_v2 gnomad_v4 PMID:25741868
PM1 N/A Not applicable: variant lies in intronic sequence and does not alter any protein domain or mutational hotspot.
PMID:25741868 PMID:27734835
PM2 Met Met (Moderate): maximum subpopulation allele frequency 0.00468% (gnomAD v2.1), far below the 0.1% threshold, with zero homozygotes.
gnomad_v2 gnomad_v4 gnomad_canada PMID:27734835 PMID:25741868
PM3 N/A Not applicable: Birt-Hogg-Dubé syndrome is autosomal dominant, so the recessive in-trans premise of PM3 does not apply.
PMID:25741868 PMID:27734835 PMID:28499369
PM4 Not met Not met: exon 11 skipping removes 124 bp, not a multiple of 3, so the consequence is out-of-frame (null), not an in-frame protein length change.
PMID:27734835 spliceai pvs1_variant_assessment
PM5 N/A Not applicable: intronic deletion with no amino acid change, so no missense residue exists for comparison.
PMID:25741868 PMID:27734835
PM6 Not assessed Not assessed: no source reports an assumed de novo occurrence or parental samples for this variant.
PMID:25741868
PP1 Met Met (Supporting): co-segregation reported in multiple affected family members across at least two independent BHD families (Rossing 2017, Bartram 2017). Flagged for human review: confirm segregation counts from the original family reports.
PMID:27734835 PMID:28499369 PMID:25741868
PP2 N/A Not applicable: criterion applies only to missense variants; this is an intronic splice-region deletion.
PMID:25741868 PMID:27734835
PP3 Not met Not met: SpliceAI max delta 0.00, far below the 0.2 splice-impact threshold, with no other computational evidence of a deleterious effect.
spliceai
PP4 Met Met (Supporting): carriers consistently show the highly specific Birt-Hogg-Dubé phenotype (fibrofolliculomas, lung cysts/pneumothorax, chromophobe renal cell carcinoma), a disorder with a single genetic etiology.
PMID:27734835 PMID:28499369 PMID:19802896 clinvar PMID:25741868
PP5 N/A Not applicable: no expert-panel ClinVar classification exists for this variant (0 expert-panel submissions).
clinvar PMID:25741868
BA1 Not met Not met: total allele frequency 0.00043% (gnomAD v4.1), roughly 1000-fold below the >1% BA1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: maximum allele frequency 0.00468%, far below the >0.3% BS1 threshold for this rare disorder.
gnomad_v2 gnomad_v4 PMID:35176117 PMID:27734835 PMID:25741868
BS2 Not met Not met: BHD is adult-onset with variable, age-dependent penetrance, so the early-age full-penetrance healthy-adult precondition is not satisfied.
gnomad_v2 gnomad_v4 PMID:27734835 PMID:35176117 PMID:25741868
BS3 Not met Not met: two independent minigene assays demonstrate a clear deleterious splicing effect, contradicting any no-damage functional evidence.
PMID:28499369 PMID:27734835 spliceai
BS4 Not met Not met: no affected family member without the variant is reported; available family data show co-segregation instead.
PMID:27734835 PMID:28499369
BP1 N/A Not applicable: applies only to missense variants; this is an intronic splice-region deletion.
PMID:25741868 PMID:27734835
BP2 Not met Not met: no observation of the variant in trans or cis with a second pathogenic FLCN variant is reported.
clinvar PMID:25741868 PMID:27734835 PMID:28499369
BP3 Not met Not met: variant is intronic and the demonstrated splicing consequence is out-of-frame, not an in-frame repeat-region indel.
spliceai pvs1_variant_assessment
BP4 Not assessed Not assessed: only a single computational line (SpliceAI max delta 0.00) is available, but multiple independent lines are required for BP4.
spliceai PMID:25741868
BP5 Not assessed Not assessed: no proband-level molecular workup is reported, so an alternate molecular basis can neither be shown nor excluded.
PMID:27734835 PMID:28499369 clinvar PMID:25741868
BP6 N/A Not applicable: no expert-panel benign ClinVar classification exists for this variant.
clinvar PMID:25741868
BP7 N/A Not applicable: applies only to synonymous coding variants; this is an intronic deletion.
PMID:25741868
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