Variant classification summary

NM_000136.3:c.456+4A>T

FANCC · NP_000127.2:p.? · NM_000136.3

GRCh37: chr9:97934315 T>A · GRCh38: chr9:95172033 T>A

Gene: FANCC Transcript: NM_000136.3

Final call

VUS

PS3 supporting PM3 moderate PP3 moderate

Variant details

Gene

FANCC

Transcript

NM_000136.3

Protein

NP_000127.2:p.?

gnomAD AF

0.0001715268070060028 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: variant-specific RT-PCR showed abnormal FANCC splicing, including exon 6 skipping.

2

PM3 moderate: the variant was in trans with a maternal FANCC deletion in an affected patient.

3

PP3 moderate: SpliceAI maximum delta 0.895 supports splice disruption.

Final determination: Under the generic ACMG/AMP 2015 fallback, two moderate criteria plus one supporting criterion do not meet a pathogenic or likely pathogenic combination rule, so the call is 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	N/A	Not applicable: c.456+4A>T is an intronic +4 splice variant, outside the rule's named canonical +/−1 or 2 splice-site locations.	pvs1_variant_assessment pvs1_gene_context PMID:23613520
PS1	N/A	Not applicable: c.456+4A>T is intronic with protein consequence p.?, so no amino-acid change exists for PS1 comparison.
PS2	Not met	Not met: the exact variant was reported as a paternal mutation in affected patient FA10, demonstrating inheritance rather than de novo occurrence.	PMID:23613520
PS3	Met	Met at supporting strength: RT-PCR in FA10 showed c.456+4A>T produced alternatively spliced FANCC transcripts, including exon 6 skipping.	PMID:23613520
PS4	Not assessed	Not assessed: no verified affected/control counts, OR or RR, and 95% CI were available to test the >5.0 PS4 threshold and exclusion of 1.0.	PMID:7492758 gnomad_v4
PM1	N/A	Not applicable: c.456+4A>T is intronic with protein consequence p.?, not a missense change located in a protein domain or hotspot.
PM2	Not met	Not met: gnomAD v4.1 observed AF is 0.000171527, above the generic PM2 cutoff of 0.0001, and the variant is also present in v2.1.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Met	Met: an affected FA10 patient carried c.456+4A>T paternal in trans with a nonexpressed maternal 8.5-kb FANCC deletion.	PMID:23613520
PM4	N/A	Not applicable: c.456+4A>T is intronic with p.? and is not an in-frame insertion, in-frame deletion, or stop-loss variant.	pvs1_variant_assessment
PM5	N/A	Not applicable: c.456+4A>T is intronic with protein consequence p.?, so no novel missense residue exists for PM5 comparison.
PM6	Not met	Not met: the exact variant was documented as paternal in affected patient FA10, so it is inherited rather than assumed de novo.	PMID:23613520
PP1	Not assessed	Not assessed: one affected patient is reported, but no multiple affected relatives or informative meioses are provided for co-segregation.	PMID:23613520
PP2	N/A	Not applicable: c.456+4A>T is intronic with protein consequence p.?, not a missense variant eligible for PP2.
PP3	Met	Met, moderate: SpliceAI max delta 0.895 exceeds the generic PP3 moderate threshold of >=0.5 for intronic or splice-region variants.	spliceai
PP4	Not assessed	Not assessed: the patient's phenotype and family history were not supplied, and Fanconi anemia has multiple genetic etiologies.
PP5	Not met	Not met: ClinVar reports Pathogenic but has 0 expert-panel submissions, so the required expert-panel trigger for PP5 is absent.	clinvar PMID:10666230 PMID:8128956
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.169e-05, far below the generic BA1 threshold of 0.05, despite an Ashkenazi Jewish point estimate of 0.00680994.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.169e-05, below the generic BS1 default of 0.01 and the Ashkenazi Jewish point estimate of 0.00680994.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD reports zero homozygotes in both v2.1 and v4.1, so no healthy-adult homozygous observation supports BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no study demonstrates preserved FANCC function or splicing for c.456+4A>T; the available RNA result instead shows aberrant splicing.	PMID:23613520
BS4	Not assessed	Not assessed: no affected relatives with negative variant testing or family-level non-segregation data are reported.
BP1	N/A	Not applicable: c.456+4A>T is intronic with protein consequence p.?, not a missense variant eligible for BP1.
BP2	Not met	Not met: the documented configuration is trans in recessive FANCC disease, not dominant-disorder trans or pathogenic-variant cis as required by BP2.	PMID:23613520
BP3	N/A	Not applicable: c.456+4A>T is intronic and is not an in-frame deletion or insertion in a repetitive protein-coding region.	pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI max delta 0.895 exceeds the generic BP4 supporting threshold of <=0.1 for an intronic splice-region variant.	spliceai
BP5	Not assessed	Not assessed: no case with an alternate molecular basis for the reported disease was documented.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification was present; ClinVar instead reports Pathogenic with 0 expert-panel submissions.	clinvar
BP7	N/A	Not applicable: the variant is intronic at c.456+4, whereas BP7 applies only to synonymous variants.

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