NM_018062.3:c.580A>G (p.Ile194Val) is a missense variant in exon 8 of FANCL, a Fanconi anemia pathway gene. This variant is present in population databases: 68 of 282,780 alleles in gnomAD v2.1 (AF 0.024%) and 235 of 1,614,080 alleles in gnomAD v4.1 (AF 0.015%), including one homozygous individual in v4.1.1 Multiple in silico predictors support a benign effect: REVEL score 0.049, BayesDel score -0.583, and SpliceAI max delta score 0.00.2 The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp Genetics, Fulgent Genetics) with no expert panel classification.3 No variant-specific functional studies, case-control data, de novo observations, or segregation data are available. The only criterion met is BP4 (supporting benign) based on consistent in silico predictions of no impact.4 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): a single supporting benign criterion (BP4) is insufficient to classify as likely benign. The variant remains a variant of uncertain significance.5
FANCL
Final classification
VUS
FANCL c.580A>G · p.Ile194Val
FANCL
NM_018062.3:c.580A>G (p.Ile194Val) is a missense variant in exon 8 of FANCL, a Fanconi anemia pathway gene.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting benign; combination = 1 supporting benign, which maps to VUS.
Classification rationale
BP4
VUS
FANCL c.580A>G
BP4
→
VUS
2
revelbayesdelspliceai ↗
4
revelbayesdelspliceai ↗
Gene diagram
· NM_018062.3 · variants mapped to exon structure
FANCL
NM_018062.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
Multiple lines of computational evidence uniformly predict no impact on the gene product. REVEL score 0.049 (strongly benign-predicting), BayesDel score -0.583 (benign-predicting), and SpliceAI max delta 0.00 (no predicted splicing impact). All available in silico tools support a benign interpretation.
REVEL 0.049 (benignwell below 0.5 threshold)BayesDel -0.583 (benign
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon that produces the same amino acid change and is known to be pathogenic.
PS2
No de novo data are available for this variant.
PS3
No variant-specific functional studies were identified.
PS4
No case-control studies or statistical enrichment data are available for this variant.
PM1
Residue 194 is not located within a statistically significant mutational hotspot and does not lie in a well-established functional domain where pathogenic variants cluster and benign variants are absent.
PM2
This variant is present in population databases.
PM6
No de novo data are available for this variant.
PP1
No segregation data are available for this variant.
PP2
Insufficient gene-level constraint data are available to determine whether FANCL has a low rate of benign missense variation.
PP3
Multiple in silico predictors uniformly suggest a benign effect.
PP4
No specific patient phenotype information is available for independent evaluation.
PP5
PP5 requires a reputable source to have classified the variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in any general population.
BS1
BS1 requires an allele frequency >0.3% for a disorder expected to be rarer than the observed frequency.
BS2
BS2 requires observation in a healthy adult homozygous state for a fully penetrant recessive disorder with early onset.
BS3
BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect.
BS4
No segregation data are available.
BP1
BP1 applies to missense variants in genes where only truncating variants cause disease.
BP2
BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
BP5
BP5 requires identification of an alternate molecular basis for disease in a case harboring this variant.
BP6
BP6 requires a reputable source to classify the variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000145594; MAF= 0.01456%, 235/1614080 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00138343; MAF= 0.13834%, 126/91078 alleles, homozygotes = 0); grpmax FAF= 0.00118704.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00024047; MAF= 0.02405%, 68/282780 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00153535; MAF= 0.15353%, 47/30612 alleles, homozygotes = 0); grpmax FAF= 0.00118549.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.015%
· 235 / 1,614,080
1 hom · FAF 0.12%
1 hom · FAF 0.12%
South Asian 126 / 91,078 |
0.14% |
African/African American 26 / 75,026 |
0.035% |
Remaining individuals 15 / 62,504 |
0.024% |
Middle Eastern 1 / 6,060 |
0.017% |
East Asian 6 / 44,870 |
0.013% |
Admixed American 6 / 60,002 |
0.01% |
European (non-Finnish) 54 / 1,179,986 |
0.0046% 1 hom |
European (Finnish) 1 / 64,038 |
0.0016% |
+ 2 not observed (Amish, Ashkenazi Jewish)
gnomAD v2.1
0.024%
· 68 / 282,780
0 hom · FAF 0.12%
0 hom · FAF 0.12%
South Asian 47 / 30,612 |
0.15% |
African/African American 7 / 24,970 |
0.028% |
East Asian 5 / 19,950 |
0.025% |
Admixed American 5 / 35,440 |
0.014% |
Remaining individuals 1 / 7,222 |
0.014% |
European (non-Finnish) 3 / 129,102 |
0.0023% |
+ 2 not observed (Ashkenazi Jewish, European (Finnish))
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 (2 clinical laboratories). (ClinVarID = 840033)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.049. BayesDel score = -0.583145.
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. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR