This missense variant (NM_001113378.1:c.2348A>G, p.Asp783Gly) in FANCI is extremely rare in population databases (gnomAD v4.1 AF=0.00019%, 3/1,614,154 alleles, 0 homozygotes), meeting PM2 at supporting level.1 Multiple in silico tools predict no deleterious effect (REVEL 0.316, BayesDel -0.140, SpliceAI max delta 0.03), meeting BP4 at supporting level.2 No functional studies, segregation data, de novo reports, or pathogenic same-residue comparators were identified. The variant is classified as Uncertain Significance in ClinVar by a single submitter.3 Under ACMG/AMP 2015 generic combination rules, the evidence is conflicting and insufficient for classification: one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting). The variant is classified as Uncertain Significance (VUS).4
FANCI
Final classification
VUS
FANCI c.2348A>G · p.Asp783Gly
FANCI
This missense variant (NM_001113378.1:c.2348A>G, p.Asp783Gly) in FANCI is extremely rare in population databases (gnomAD v4.1 AF=0.00019%, 3/1,614,154 alleles, 0 homozygotes), meeting PM2 at supporting level.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCI c.2348A>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
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
supporting
Pathogenic
The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,614,154 alleles, 0 homozygotes), well below the 0.1% threshold for PM2 at supporting level.
gnomAD v2.1: absentgnomAD v4.1: AF=1.86e-06 (0.00019%)3/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score is 0.316 (below pathogenic thresholds), BayesDel is -0.140 (benign prediction), and SpliceAI predicts no significant splicing impact (max delta=0.03).
REVEL: 0.316 (not predicted pathogenic)BayesDel: -0.140 (benign)SpliceAI max delta: 0.03 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No evidence was identified that a different nucleotide change at c.2348 resulting in the same amino acid substitution (p.Asp783Gly) has been classified as pathogenic.
PS2
No de novo data (with confirmed maternity and paternity) are available for this variant.
PS3
No functional studies directly testing NM_001113378.1:c.2348A>G or a systematically characterized range including p.Asp783Gly were identified.
PS4
No case-control studies or patient cohort data with variant-specific prevalence are available.
PM1
The variant is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no evidence was identified that p.Asp783 lies within a well-characterized functional domain with established pathogenic missense constraint specific to FANCI.
PM5
No different missense variant at the same amino acid residue (p.Asp783) was identified in ClinVar with a pathogenic classification.
PM6
No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1
No co-segregation data are available for this variant in affected families.
PP2
Insufficient data to determine whether FANCI has a low rate of benign missense variation; HCI prior probability was not available for this gene.
PP3
Multiple in silico tools do not support a deleterious effect: REVEL score is 0.316 (below commonly used thresholds for pathogenicity), BayesDel is -0.140 (benign prediction), and SpliceAI predicts no significant splicing impact (max delta=0.03).
PP4
No patient phenotype or family history data are available for this variant.
PP5
The variant is classified as Uncertain Significance in ClinVar by a single clinical laboratory (Labcorp Genetics, SCV000751933), not as pathogenic by any reputable source.
Benign
BA1
The allele frequency in gnomAD v4.1 is 0.00019%, far below the 1% threshold required for BA1.
BS1
The allele frequency in gnomAD v4.1 is 0.00019%, below the 0.3% threshold for BS1.
BS2
No data are available regarding observation of this variant in healthy adults for a disorder where full penetrance is expected at an early age.
BS3
No functional studies demonstrating a lack of damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation data are available to demonstrate lack of co-segregation with disease in affected families.
BP1
While FANCI loss-of-function is a recognized disease mechanism, missense variants in FANCI have also been associated with disease in the literature (e.g., FANCI is reported among genes with functionally deleterious germline mutations in cancer predisposition).
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant disorder.
BP5
No case has been reported where this variant was found in an individual with an alternative molecular basis for disease.
BP6
No reputable source classifies this variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85856e-06; MAF= 0.00019%, 3/1614154 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54236e-06; MAF= 0.00025%, 3/1180006 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,154
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (non-Finnish) 3 / 1,180,006 |
0.00025% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 526429)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.316. BayesDel score = -0.140336.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108096565, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
19888064 ↗
ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR