NM_033084.4:c.206-1G>A

FANCD2 · NP_149075.2:p.? · NM_033084.4

GRCh37: chr3:10076152 G>A · GRCh38: chr3:10034468 G>A

Gene: FANCD2 Transcript: NM_033084.4

Final call

Likely Pathogenic

PVS1 strong PM2 moderate

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one Strong criterion (PVS1) plus one Moderate criterion (PM2) meets the threshold for Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No known pathogenic variant at the same nucleotide position with the same predicted amino acid change is available for comparison. This canonical splice variant has no established pathogenic comparator.
PS2	Not assessed	No de novo occurrence data are available for NM_033084.4:c.206-1G>A. The variant has not been reported in any publication or clinical database.
PS3	Not assessed	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	Not assessed	No case-control studies or prevalence data comparing affected versus unaffected individuals are available for this variant.
PS5	Not assessed	No family-based segregation or phase data are available for NM_033084.4:c.206-1G>A.
PM1	Not assessed	No well-established mutational hotspot or critical functional domain has been identified for FANCD2 at the c.206-1 splice acceptor region. The variant is intronic and does not map to a characterized functional domain.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	NM_033084.4:c.206-1G>A is a canonical splice variant with unknown protein consequence (p.?). No same-residue missense comparator is available; classic PM5 semantics cannot be applied.
PM6	Not assessed	No de novo occurrence data, parental confirmation, or maternity/paternity testing is available for NM_033084.4:c.206-1G>A.
PP1	Not assessed	No cosegregation data are available for NM_033084.4:c.206-1G>A. No family studies have been reported.
PP2	N/A	NM_033084.4:c.206-1G>A is a canonical splice site variant, not a missense change. PP2 applies only to missense variants in genes with low tolerance for missense variation.
PP3	N/A	SpliceAI predicts a deleterious splice effect (max delta score 0.95 with acceptor loss 0.95, donor loss 0.67). BayesDel score is 0.66 (damaging). However, the ClinGen SVI PVS1 framework (PMC6185798) explicitly states that in silico splice prediction evidence should not be double-counted with PVS1 for canonical splice variants. Since PVS1 is applied at strong weight for the splice defect, PP3 for the same splice prediction evidence is not stacked.	spliceai bayesdel
PP4	Not assessed	No patient phenotype information is available to assess whether the clinical presentation is specific for FANCD2-related disease.
PP5	Not assessed	The variant is absent from ClinVar. No reputable clinical source has reported NM_033084.4:c.206-1G>A as pathogenic or likely pathogenic.	clinvar
BA1	Not met	NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available on observation of this variant in healthy adult individuals. FANCD2-related Fanconi anemia typically presents in childhood; adult-onset phenotypes are not well characterized for this variant.
BS3	Not assessed	No functional studies demonstrating a benign effect of NM_033084.4:c.206-1G>A on splicing or protein function have been identified.
BS4	Not assessed	No segregation data are available to assess whether the variant fails to cosegregate with disease in affected families.
BP1	N/A	NM_033084.4:c.206-1G>A is a canonical splice site variant, not a missense variant. BP1 applies only to missense variants in genes where truncating variants are the primary disease mechanism.
BP2	Not assessed	No data are available on whether NM_033084.4:c.206-1G>A has been observed in trans with a known pathogenic FANCD2 variant.
BP3	N/A	NM_033084.4:c.206-1G>A is a single nucleotide substitution, not an in-frame insertion or deletion.
BP4	Not met	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. No benign computational prediction is available to support BP4.	spliceai bayesdel
BP5	Not assessed	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	Not assessed	The variant is absent from ClinVar. No reputable source has classified NM_033084.4:c.206-1G>A as benign or likely benign.	clinvar
BP7	N/A	NM_033084.4:c.206-1G>A is a canonical splice site variant, not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact.

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.