Variant classification summary

NM_033084.4:c.3560+2T>A

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

GRCh37: chr3:10130228 T>A · GRCh38: chr3:10088544 T>A

Gene: FANCD2 Transcript: NM_033084.4

Final call

VUS

PM2 supporting

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent (AF 0) from gnomAD v2.1, v4.1, and gnomAD-Canada — below the <0.1% recessive-disorder threshold.

2

Overall classification: VUS — a single supporting criterion meets no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold under the generic ACMG/AMP 2015 framework.

Final determination: Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), the single applied supporting criterion (PM2) satisfies none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Not assessed	Not assessed: insufficient evidence was available to evaluate whether this splice variant causes loss of function.
PS1	N/A	Not applicable: as a splice-site variant producing no altered amino acid, no established pathogenic missense change exists to compare.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental-testing data were available to confirm or exclude a de novo origin.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay evidence was available; the only relevant datum was an in silico splice prediction, not a functional assay.	spliceai
PS4	Not assessed	Not assessed: no case-control or cohort data reported this variant — it is absent from ClinVar, gnomAD, and the literature.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules final_classification_framework
PM1	N/A	Not applicable: as a splice-site variant producing no altered residue, no mutational hotspot or critical-domain membership can be evaluated.	generic_acmg_combination_rules
PM2	Met	Met (supporting): variant is absent (AF 0) from gnomAD v2.1, v4.1, and gnomAD-Canada, below the <0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no proband, second-allele, or phase data were available to test for a pathogenic trans counterpart.	generic_acmg_combination_rules
PM4	N/A	Not applicable: as a splice-site variant, no protein length change occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: as a splice-site variant producing no missense change, no pathogenic missense comparator exists at this residue.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental testing data were available to evaluate an assumed de novo occurrence.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree or family segregation data were available.	clinvar generic_acmg_combination_rules
PP2	N/A	Not applicable: as a splice-site variant producing no missense change, the gene's missense-constraint properties are not relevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.99 predicts near-certain splice impact, but this same prediction is counted under PVS1 and cannot be double-counted as PP3.	spliceai bayesdel pvs1_generic_framework generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family history data were available to assess phenotype specificity.	generic_acmg_combination_rules final_classification_framework pvs1_gene_context
PP5	Not met	Not met: ClinVar has no record for this variant, so no expert-panel Pathogenic or Likely pathogenic classification exists to support PP5.	clinvar final_classification_framework
BA1	Not met	Not met: variant is absent (AF 0) from population databases, far below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: variant is absent (AF 0), far below the >0.3% BS1 threshold expected for this very rare recessive disorder.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no homozygous observations exist — the variant is absent from all queried population databases, and biallelic loss causes severe early-onset disease.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established functional study demonstrating a benign effect was available for this variant.	spliceai
BS4	Not assessed	Not assessed: no family segregation testing was performed, so lack of segregation could not be observed.	clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BP1	N/A	Not applicable: as a splice-site variant producing no missense change, the truncating-variant mechanism criterion does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or phase-resolved observation was available to evaluate a cis/trans configuration.	generic_acmg_combination_rules
BP3	N/A	Not applicable: as a splice-site variant, no in-frame length change in a repetitive region occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.99 predicts near-certain splice impact, the opposite of the no-impact evidence BP4 requires.	spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband genotype or diagnostic data were available to evaluate an alternative molecular cause.	clinvar generic_acmg_combination_rules final_classification_framework
BP6	Not met	Not met: ClinVar has no record for this variant, so no expert-panel Benign or Likely benign classification exists to support BP6.	clinvar final_classification_framework
BP7	N/A	Not applicable: this is not a synonymous variant — it alters the encoded protein sequence.	generic_acmg_combination_rules

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