NM_001113378.1:c.1689T>G

FANCI · NP_001106849.1:p.(Ser563Arg) · NM_001113378.1

GRCh37: chr15:89826472 T>G · GRCh38: chr15:89283241 T>G

Gene: FANCI Transcript: NM_001113378.1

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

FANCI

Transcript

NM_001113378.1

Protein

NP_001106849.1:p.(Ser563Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

FANCI c.1689T>G (p.Ser563Arg) is a missense variant absent from gnomAD v2.1 and v4.1 population databases (PM2).

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).

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.

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), this variant is classified as a Variant of 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	Missense variant (p.Ser563Arg) does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Ser563Arg) has been reported in ClinVar or the literature.	clinvar
PS2	Not met	No de novo data identified; this variant has not been reported as a confirmed de novo occurrence with maternity and paternity confirmed.
PS3	Not met	No variant-specific functional data or systematic functional characterization of the region encompassing residue 563 of FANCI was identified.	oncokb
PS4	Not met	Variant has not been reported in affected individuals in the literature, and no case-control data are available to evaluate enrichment in affected individuals.
PS5	Not met	No pathogenic variant at codon 563 of FANCI has been reported in ClinVar or the literature with a different amino acid change.	clinvar
PM1	Not met	Residue 563 of FANCI is not located in a known mutational hotspot or a well-characterized critical functional domain supported by the literature.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same codon (Ser563) with a different amino acid change has been reported in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo data identified; this variant has not been reported as a de novo occurrence without confirmed parentage.
PP1	Not met	No co-segregation data are available for this variant.
PP2	Not met	Insufficient evidence that FANCI has a low rate of benign missense variation; no gene-specific missense constraint metric was available.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical information is available for evaluation.
PP5	Not met	This variant is absent from ClinVar; no expert panel or reputable source classification is available.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, well below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	Variant is absent from gnomAD and has not been observed in a homozygous or hemizygous state in healthy adults.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no damaging effect for p.Ser563Arg in FANCI.
BS4	Not met	No family segregation data are available for analysis.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No data on variants observed in trans with a pathogenic variant in FANCI are available.
BP3	N/A	In-frame insertions/deletions in a non-repeat region are not present; this variant is a single-nucleotide substitution.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease.
BP6	Not met	This variant is absent from ClinVar; no expert panel or reputable source benign classification is available.	clinvar
BP7	N/A	This is a missense variant (p.Ser563Arg), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact.
PM3	N/A	No data available for variants observed in trans with a pathogenic variant in this recessive disorder gene.
PM4	N/A	No protein length change is caused by this substitution variant; PM4 applies to non-repeat in-frame insertions/deletions and stop-loss variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.