NM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1 (PVS1_Strong). FANCD2 loss of function is an established germline disease mechanism for Fanconi anemia and cancer predisposition, supporting PVS1 at strong weight under PMC6185798.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Moderate), consistent with a rare pathogenic variant in a gene with established germline disease association.2 SpliceAI predicts a strong splice effect (max delta 0.95, acceptor loss 0.95) and BayesDel scores 0.66 (damaging). These in silico predictions support pathogenicity but are not stacked as PP3 per PMC6185798 guidance to avoid double-counting with PVS1 for canonical splice variants.3 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one Strong criterion (PVS1) plus one Moderate criterion (PM2) meets the threshold for Likely Pathogenic.4
FANCD2
Final classification
Likely Pathogenic
FANCD2 c.206-1G>A · p.?
FANCD2
NM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1 (PVS1_Strong). FANCD2 loss of function is an established germline disease mechanism for Fanconi anemia and cancer predisposition, supporting PVS1 at strong weight under PMC6185798.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 moderate; combination = 1 strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
FANCD2 c.206-1G>A
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
3
spliceai ↗bayesdel
4
generic_acmg_combination_rules
Gene diagram
· NM_033084.4 · variants mapped to exon structure
FANCD2
NM_033084.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95). BayesDel score = 0.66.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
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.
Sources & reference links