NM_001113378.1:c.2348A>G

FANCI · NP_001106849.1:p.(Asp783Gly) · NM_001113378.1

GRCh37: chr15:89837120 A>G · GRCh38: chr15:89293889 A>G

Gene: FANCI Transcript: NM_001113378.1

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FANCI

Transcript

NM_001113378.1

Protein

NP_001106849.1:p.(Asp783Gly)

gnomAD AF

1.85855872488003e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Multiple in silico tools predict no deleterious effect (REVEL 0.316, BayesDel -0.140, SpliceAI max delta 0.03), meeting BP4 at supporting level.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination 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	N/A	This is a missense variant (c.2348A>G, p.Asp783Gly), not a null variant (nonsense, frameshift, or canonical splice site). The generic PVS1 framework does not apply to missense substitutions.	pvs1_variant_assessment
PS1	Not met	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	Not met	No de novo data (with confirmed maternity and paternity) are available for this variant.
PS3	Not met	No functional studies directly testing NM_001113378.1:c.2348A>G or a systematically characterized range including p.Asp783Gly were identified. OncoKB reports unknown oncogenic effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control studies or patient cohort data with variant-specific prevalence are available. The literature identified through ClinVar consists of general population carrier screening guidelines that do not report case counts for this variant.	PMID:18197057 PMID:19888064 PMID:26389210 PMID:26389258 PMID:26389333
PS5	Not met	No different missense variant at the same amino acid residue (p.Asp783) has been reported as pathogenic. PM5 candidate search returned zero same-residue comparators in ClinVar.	pm5_candidates
PM1	Not met	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.	oncokb
PM2	Met	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 gnomad_v4
PM3	N/A	PM3 was skipped by pre-adjudication directive; variant-specific trans data are not available for recessive disorder assessment.
PM4	N/A	PM4 was skipped by pre-adjudication directive; variant is a single-nucleotide substitution, not an in-frame indel or stop-loss variant.
PM5	Not met	No different missense variant at the same amino acid residue (p.Asp783) was identified in ClinVar with a pathogenic classification. Automated PM5 candidate search returned zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant in affected families.
PP2	Not met	Insufficient data to determine whether FANCI has a low rate of benign missense variation; HCI prior probability was not available for this gene.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for this variant.
PP5	Not met	The variant is classified as Uncertain Significance in ClinVar by a single clinical laboratory (Labcorp Genetics, SCV000751933), not as pathogenic by any reputable source.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 0.00019%, far below the 1% threshold required for BA1.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 0.00019%, below the 0.3% threshold for BS1.	gnomad_v4
BS2	Not met	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	Not met	No functional studies demonstrating a lack of damaging effect on protein function or splicing have been identified for this variant.
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease in affected families.
BP1	Not met	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). BP1 applies specifically to genes where primarily truncating variants cause disease; FANCI does not meet this criterion.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant disorder.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame insertion/deletion in a repetitive region.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No case has been reported where this variant was found in an individual with an alternative molecular basis for disease.
BP6	Not met	No reputable source classifies this variant as benign. ClinVar classification is Uncertain Significance from a single submitter.	clinvar
BP7	N/A	This is a missense variant (c.2348A>G, p.Asp783Gly), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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