Classification rationale

PM2 BP4 VUS

FANCI c.1689T>G

FANCI c.1689T>G (p.Ser563Arg) is a missense variant absent from gnomAD v2.1 and v4.1 population databases (PM2).¹ Multiple in silico tools predict a benign effect: REVEL score 0.093, BayesDel score -0.448, and SpliceAI predicts no splicing impact (max delta 0.11) (BP4).² This variant is absent from ClinVar and has not been reported in the literature as a de novo event or in affected individuals; no functional studies, segregation data, or case-control analyses are available.³ With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), this variant is classified as a Variant of Uncertain Significance (VUS).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

Gene diagram · NM_001113378.1 · variants mapped to exon structure

FANCI NM_001113378.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), with an allele frequency well below the 0.1% threshold for PM2.

Absent from gnomAD v2.1 (0/~250000 alleles). Absent from gnomAD v4.1 (0/~800000 alleles). Allele frequency 0%.

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence predict a benign effect: REVEL score 0.093 (benign), BayesDel score -0.448 (benign), and SpliceAI max delta score 0.11 (no significant splice impact).

REVEL: 0.093 (strongly benignthreshold for damaging ≥0.5). BayesDel: -0.448 (benignthreshold for damaging >0). SpliceAI: max delta 0.11 (no splicing alteration

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No known pathogenic variant with the same amino acid change (p.Ser563Arg) has been reported in ClinVar or the literature.

PS2 No de novo data identified; this variant has not been reported as a confirmed de novo occurrence with maternity and paternity confirmed.

PS3 No variant-specific functional data or systematic functional characterization of the region encompassing residue 563 of FANCI was identified.

PS4 Variant has not been reported in affected individuals in the literature, and no case-control data are available to evaluate enrichment in affected individuals.

PM1 Residue 563 of FANCI is not located in a known mutational hotspot or a well-characterized critical functional domain supported by the literature.

PM5 No pathogenic missense variant at the same codon (Ser563) with a different amino acid change has been reported in ClinVar.

PM6 No de novo data identified; this variant has not been reported as a de novo occurrence without confirmed parentage.

PP1 No co-segregation data are available for this variant.

PP2 Insufficient evidence that FANCI has a low rate of benign missense variation; no gene-specific missense constraint metric was available.

PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.093 (below 0.5 damaging threshold), BayesDel score -0.448 (negative, indicating benign), and SpliceAI max delta score 0.11 (no significant splice impact).

PP4 No patient phenotype or clinical information is available for evaluation.

PP5 This variant is absent from ClinVar; no expert panel or reputable source classification is available.

Benign

BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, well below the 1% threshold for BA1.

BS1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, below the 0.3% threshold for BS1.

BS2 Variant is absent from gnomAD and has not been observed in a homozygous or hemizygous state in healthy adults.

BS3 No well-established functional studies demonstrate no damaging effect for p.Ser563Arg in FANCI.

BS4 No family segregation data are available for analysis.

BP1 While FANCI loss-of-function variants are reported in disease (e.g., Fanconi Anemia), missense variants are also a recognized mechanism of disease; the gene is not exclusively associated with truncating pathogenic variants.

BP2 No data on variants observed in trans with a pathogenic variant in FANCI are available.

BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease.

BP6 This variant is absent from ClinVar; no expert panel or reputable source benign classification is available.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.093. BayesDel score = -0.448202.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCI, a DNA repair protein in the Fanconi Anemia complementation group, is infrequently altered in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots