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
PVS1PM2
FANCD2
c.206-1G>A
p.?
This variant
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 applied · 18 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
strong
Pathogenic
NM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1. FANCD2 loss of function is an established disease mechanism for Fanconi anemia and cancer predisposition. Under the ClinGen SVI PVS1 decision framework (PMC6185798), canonical ±1,2 splice variants in genes with established LOF disease mechanism are assigned PVS1 at strong weight.
FANCD2 germline loss of function is a well-established disease mechanism supported by multiple publications (PMID:27285993PMID:29659569PMID:29376519)
✓
PM2
moderate
Pathogenic
NM_033084.4:c.206-1G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. The allele frequency is 0.0% across all population databases, meeting the PM2 threshold of <0.1% for a gene with established germline disease association.
Absent from gnomAD v2.1 (AC=0 across all populations)Absent from gnomAD v4.1 (AC=0 across all populations)Absent from gnomAD-Canada v1.0 (AC=0)
Assessed · not applied
· 3 not met · 15 not assessed
Pathogenic
PS1
No known pathogenic variant at the same nucleotide position with the same predicted amino acid change is available for comparison.
PS2
No de novo occurrence data are available for NM_033084.4:c.206-1G>A.
PS3
No functional studies evaluating the impact of NM_033084.4:c.206-1G>A on splicing or protein function have been identified in the literature.
PS4
No case-control studies or prevalence data comparing affected versus unaffected individuals are available for this variant.
PM1
No well-established mutational hotspot or critical functional domain has been identified for FANCD2 at the c.206-1 splice acceptor region.
PM6
No de novo occurrence data, parental confirmation, or maternity/paternity testing is available for NM_033084.4:c.206-1G>A.
PP1
No cosegregation data are available for NM_033084.4:c.206-1G>A.
PP4
No patient phenotype information is available to assess whether the clinical presentation is specific for FANCD2-related disease.
PP5
The variant is absent from ClinVar.
Benign
BA1
NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data are available on observation of this variant in healthy adult individuals.
BS3
No functional studies demonstrating a benign effect of NM_033084.4:c.206-1G>A on splicing or protein function have been identified.
BS4
No segregation data are available to assess whether the variant fails to cosegregate with disease in affected families.
BP2
No data are available on whether NM_033084.4:c.206-1G>A has been observed in trans with a known pathogenic FANCD2 variant.
BP4
In silico predictions are uniformly damaging: SpliceAI predicts strong splice disruption (max delta score 0.95), and BayesDel score is 0.66, exceeding the damaging threshold.
BP5
No case has been identified where NM_033084.4:c.206-1G>A is observed in an individual with an alternative molecular cause for the phenotype.
BP6
The variant is absent from ClinVar.
N/A · 6
PM5 · PP2 · PP3 · BP1 · BP3 · BP7
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