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FANCIc.1689T>GUncertain significance
Print report
Variant interpretation report

FANCI c.1689T>G, p.Ser563Arg

NM_001113378.1:c.1689T>G NP_001106849.1:p.(Ser563Arg) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About FANCI

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.110 maximum delta

Recorded SpliceAI maximum delta score: 0.110. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0/~250
  • 000 alleles). Absent from gnomAD v4.1 (0/~800
  • 000 alleles). Allele frequency 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.093 (strongly benign
  • threshold for damaging ≥0.5). BayesDel: -0.448 (benign
  • threshold for damaging >0). SpliceAI: max delta 0.11 (no splicing alteration
  • threshold for significant ≥0.2).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No known pathogenic variant with the same amino acid change (p.Ser563Arg) has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar
  • no pathogenic variant at codon 563 with the same amino acid substitution was identified.
Still missing
  • No prior classification of any variant producing p.Ser563Arg in FANCI.
Sources
clinvar ↗
PS2 No de novo data identified; this variant has not been reported as a confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
  • No de novo reports found in ClinVar
  • literature
  • or any evidence source for this variant.
Still missing
  • No parental testing data available.
PS3 No variant-specific functional data or systematic functional characterization of the region encompassing residue 563 of FANCI was identified. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No publications performing saturation mutagenesis
  • CRISPR tiling screens
  • or systematic truncation series covering residue 563 were identified.
Still missing
  • No functional studies directly testing p.Ser563Arg or systematically characterizing the surrounding region of FANCI.
Sources
oncokb ↗
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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD population databases. No reports in affected individuals were identified in ClinVar or the literature.
Still missing
  • No cohort prevalence data comparing affected vs. unaffected 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. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org does not identify residue 563 as statistically significant. No literature evidence places this residue in a functionally characterized critical domain.
Still missing
  • No domain-level functional characterization of the region surrounding residue 563.
PM5 No pathogenic missense variant at the same codon (Ser563) with a different amino acid change has been reported in ClinVar. Details ▾Hide ▴
Evidence considered
  • pm5_candidates identified zero same-residue comparator variants at codon 563 in ClinVar. No pathogenic variant with a different missense change at this codon exists.
Still missing
  • No pathogenic comparator at codon 563 in FANCI.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo data identified; this variant has not been reported as a de novo occurrence without confirmed parentage. Details ▾Hide ▴
Evidence considered
  • No de novo reports were identified in ClinVar
  • literature
  • or any evidence source for this variant.
Still missing
  • No de novo testing data available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or co-segregation analyses including this variant were identified.
Still missing
  • No family data available to evaluate co-segregation with disease.
PP2 Insufficient evidence that FANCI has a low rate of benign missense variation; no gene-specific missense constraint metric was available. Details ▾Hide ▴
Evidence considered
  • HCI prior probability not found for this variant. No gnomAD missense Z-score or other constraint metric was provided to support a low rate of benign missense variation in FANCI.
Still missing
  • No missense constraint metric (e.g.
  • gnomAD Z-score
  • missense depletion score) available for FANCI.
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.093 (benign). BayesDel: -0.448 (benign). SpliceAI: max delta score 0.11 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or clinical information is available for evaluation. Details ▾Hide ▴
Evidence considered
  • No patient-specific phenotype
  • family history
  • or clinical data were provided for this case.
Still missing
  • Patient phenotype and clinical context not available.
PP5 This variant is absent from ClinVar; no expert panel or reputable source classification is available. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar with zero submissions.
Still missing
  • No ClinVar classification exists for this variant.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, well below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1. Allele frequency: 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency is 0%, below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1. Allele frequency: 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 Variant is absent from gnomAD and has not been observed in a homozygous or hemizygous state in healthy adults. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • no homozygous or hemizygous observations in healthy adults.
Still missing
  • No homozygous/hemizygous count data available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrate no damaging effect for p.Ser563Arg in FANCI. Details ▾Hide ▴
Evidence considered
  • No functional characterization of p.Ser563Arg was identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific evidence.
Still missing
  • No functional studies assessing the impact of p.Ser563Arg on FANCI protein function.
BS4 No family segregation data are available for analysis. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation analyses were identified for this variant.
Still missing
  • No family data available for segregation 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. Details ▾Hide ▴
Evidence considered
  • FANCI LoF mechanism is supported for germline disease
  • but missense variants are also reported as pathogenic in the literature. The gene is not exclusively truncating.
Still missing
  • No quantitative data on the proportion of benign missense variants in FANCI.
Sources
pvs1_gene_context
BP2 No data on variants observed in trans with a pathogenic variant in FANCI are available. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data were identified for this variant.
Still missing
  • No phasing data with other FANCI pathogenic variants.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No reports of this variant co-occurring with a known pathogenic variant in a gene explaining the phenotype.
Still missing
  • No alternate molecular diagnosis data available.
BP6 This variant is absent from ClinVar; no expert panel or reputable source benign classification is available. Details ▾Hide ▴
Evidence considered
  • This variant is absent from ClinVar with zero submissions.
Still missing
  • No ClinVar classification exists for this variant.
Sources
clinvar ↗
PS5 No pathogenic variant at codon 563 of FANCI has been reported in ClinVar or the literature with a different amino acid change. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no variants at codon 563 of FANCI (Ser563). No same-codon pathogenic comparator was identified.
Still missing
  • No pathogenic comparator at codon 563 is known.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Ser563Arg) does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution classified as 'other' bucket per ClinGen SVI PVS1 framework (PMC6185798)
  • apply_generic_pvs1_framework is false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ANo data available for variants observed in trans with a pathogenic variant in this recessive disorder gene. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ANo protein length change is caused by this substitution variant; PM4 applies to non-repeat in-frame insertions/deletions and stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AIn-frame insertions/deletions in a non-repeat region are not present; this variant is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (p.Ser563Arg), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (T>G at c.1689 producing p.Ser563Arg)
  • not a synonymous change.

Identifiers

Gene
FANCI
Transcript
NM_001113378.1
Coding (HGVS c.)
NM_001113378.1:c.1689T>G
Protein (HGVS p.)
NP_001106849.1:p.(Ser563Arg)
GRCh38
chr15:89283241 T>G
GRCh37
chr15:89826472 T>G

Gene diagram

Every interpreted variant in FANCI, mapped onto the exon structure of NM_001113378.1. Select a row to find it on the plot.

FANCINM_001113378.1
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -105 bp
0.110
SpliceAI acceptor gainat +0 bp
0.000
SpliceAI donor lossat +9 bp
0.110
SpliceAI donor gainat +0 bp
0.010
Pangolin splice lossmagnitude shown
-0.160
Pangolin splice gain
0.020

Other predictors

REVEL
0.093
BayesDel
-0.448

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.093 (strongly benign
  • threshold for damaging ≥0.5). BayesDel: -0.448 (benign
  • threshold for damaging >0). SpliceAI: max delta 0.11 (no splicing alteration
  • threshold for significant ≥0.2).
Sources
revelbayesdelspliceai ↗
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.093 (benign). BayesDel: -0.448 (benign). SpliceAI: max delta score 0.11 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (p.Ser563Arg), not a synonymous variant. BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (T>G at c.1689 producing p.Ser563Arg)
  • not a synonymous change.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.110 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from 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.

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.