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FANCIc.2348A>GUncertain significance
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Variant interpretation report

FANCI c.2348A>G, p.(Asp783Gly)

NM_001113378.1:c.2348A>G NP_001106849.1:p.(Asp783Gly) 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
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

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 supporting, BP4 supporting; combination = 1 supporting + 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
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV108096565, n = 1 times).

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

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).

Met · 2

PM2 SupportingThe 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: AF=1.86e-06 (0.00019%)
  • 3/1
  • 614
  • 154 alleles
  • 0 homozygotes
  • grpmax FAF=6.8e-07.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.316 (not predicted pathogenic)
  • BayesDel: -0.140 (benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

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. Details ▾Hide ▴
Still missing
  • No alternate nucleotide change at the same position has been reported or classified.
PS2 No de novo data (with confirmed maternity and paternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports identified.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No experimental functional data for this variant or a systematically characterized range spanning codon 783.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Five publications reviewed
  • none provide variant-specific case counts or case-control data.
Still missing
  • No variant-specific case-control or cohort study data.
Sources
PMID:18197057 ↗PMID:19888064 ↗PMID:26389210 ↗PMID:26389258 ↗PMID:26389333 ↗
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. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: residue not significant
  • no functional domain characterization at codon 783.
Still missing
  • No domain-level pathogenic constraint data for codon 783 in FANCI.
Sources
oncokb ↗
PM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidates: 0 same-residue candidate variants identified.
Still missing
  • No pathogenic missense comparator at codon 783.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (with or without confirmed maternity/paternity) has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Still missing
  • No family segregation studies identified.
PP2 Insufficient data to determine whether FANCI has a low rate of benign missense variation; HCI prior probability was not available for this gene. Details ▾Hide ▴
Still missing
  • No HCI prior score or gene-level missense constraint data.
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.316
  • BayesDel: -0.140 (benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data are available for this variant. Details ▾Hide ▴
Still missing
  • No proband phenotype information available.
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. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • 1 submitter
  • criteria provided single submitter. No expert panel classification.
Sources
clinvar ↗
BA1 The allele frequency in gnomAD v4.1 is 0.00019%, far below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 0.00019% (3/1
  • 614
  • 154 alleles)
  • well below 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The allele frequency in gnomAD v4.1 is 0.00019%, below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF: 0.00019%
  • below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available.
BS3 No functional studies demonstrating a lack of damaging effect on protein function or splicing have been identified for this variant. Details ▾Hide ▴
Still missing
  • No functional studies demonstrating benign effect.
BS4 No segregation data are available to demonstrate lack of co-segregation with disease in affected families. Details ▾Hide ▴
Still missing
  • No family segregation data available.
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). BP1 applies specifically to genes where primarily truncating variants cause disease; FANCI does not meet this criterion. Details ▾Hide ▴
Evidence considered
  • FANCI LoF mechanism is established
  • but missense variants are also reported in disease context
  • does not satisfy the 'primarily truncating' threshold for BP1.
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant disorder. Details ▾Hide ▴
Still missing
  • No trans data available.
BP5 No case has been reported where this variant was found in an individual with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternative molecular cause reported in any case carrying this variant.
BP6 No reputable source classifies this variant as benign. ClinVar classification is Uncertain Significance from a single submitter. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (1 submitter)
  • no benign classification from any source.
Sources
clinvar ↗
PS5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: zero same-residue candidates identified.
Still missing
  • No pathogenic comparator variant at codon 783.
Sources
pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • variant_bucket='other'
  • apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessment
PM3 N/APM3 was skipped by pre-adjudication directive; variant-specific trans data are not available for recessive disorder assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 was skipped by pre-adjudication directive; variant is a single-nucleotide substitution, not an in-frame indel or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AVariant is a single-nucleotide substitution, not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.2348A>G, p.Asp783Gly), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 criterion does not apply.

Identifiers

Gene
FANCI
Transcript
NM_001113378.1
Coding (HGVS c.)
NM_001113378.1:c.2348A>G
Protein (HGVS p.)
NP_001106849.1:p.(Asp783Gly)
GRCh38
chr15:89293889 A>G
GRCh37
chr15:89837120 A>G
ClinVar
1373824, 526429
COSMIC
COSV108096565

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 3 / 1,614,154 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,154 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,180,006 2.5e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -56 bp
0.030
SpliceAI acceptor gainat +88 bp
0.000
SpliceAI donor lossat +108 bp
0.010
SpliceAI donor gainat +20 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.030

Other predictors

REVEL
0.316
BayesDel
-0.140

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.316 (not predicted pathogenic)
  • BayesDel: -0.140 (benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
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). Details ▾Hide ▴
Evidence considered
  • REVEL: 0.316
  • BayesDel: -0.140 (benign)
  • SpliceAI max delta: 0.03 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.2348A>G, p.Asp783Gly), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 criterion does not apply.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.316. BayesDel score = -0.140336.

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Carrier screening in individuals of Ashkenazi Jewish descent.
    Gross SJ et al. · 2008
    Guideline for carrier screening in individuals of Ashkenazi Jewish descent. Discusses Tay-Sachs disease, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C (FANCC), and other conditions prevalent in this population. FANCI and NM_001113378.1:c.2348A>G were not identified in this paper.
    Does not name this variant
    PMID 18197057 ↗
  • ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.
    2009
    ACOG Committee Opinion on carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Lists Fanconi anemia group C (FANCC) among disorders with available carrier screening. FANCI and NM_001113378.1:c.2348A>G were not identified in this paper.
    Does not name this variant
    PMID 19888064 ↗
    Quoted passage
    Carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease.
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on breast and gynecologic cancers (NCBI Bookshelf). No abstract or full text with variant-specific content was available for review. NM_001113378.1:c.2348A>G was not identified in this general reference.
    Does not name this variant
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on risk assessment and counseling (NCBI Bookshelf). No abstract or full text with variant-specific content was available for review. NM_001113378.1:c.2348A>G was not identified in this general reference.
    Does not name this variant
    PMID 26389258 ↗
  • Genetics of Skin Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on skin cancer (NCBI Bookshelf). No abstract or full text with variant-specific content was available for review. NM_001113378.1:c.2348A>G was not identified in this general reference.
    Does not name this variant
    PMID 26389333 ↗

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

gnomAD v4.1 3 / 1,614,154 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗
ClinVar 1 Uncertain significance 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

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.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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

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 previously been reported in somatic cancers (COSMIC; COSV108096565, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.