NM_018062.3:c.355G>A (p.Gly119Arg) is a missense variant in exon 5 of FANCL, a gene associated with autosomal recessive Fanconi anemia. PVS1 is not applicable as this is not a null variant.1 This variant is extremely rare in population databases, with an allele frequency of 7.96e-06 (0.0008%) in gnomAD v2.1 and 6.21e-07 (0.00006%) in gnomAD v4.1, meeting PM2 at supporting level.2 Multiple computational predictors (REVEL 0.104, BayesDel -0.400665, SpliceAI max delta 0.03) concordantly suggest a benign effect, meeting BP4 at supporting level.3 The variant has been reported in ClinVar as uncertain significance by two clinical laboratories (ClinVar ID 653483). No pathogenic or benign assertions exist from expert panels.4 Functional data, segregation analysis, de novo observations, case-control studies, and variant-specific literature are all absent for this variant. No publications among the seven reviewed mention NM_018062.3:c.355G>A.5 The balanced evidence profile (PM2_supporting vs. BP4_supporting) results in a net score of zero, consistent with a classification of uncertain significance under ACMG/AMP 2015 generic rules.6
FANCL
Final classification
VUS
PM2BP4
FANCL
c.355G>A
p.Gly119Arg
This variant
NM_018062.3:c.355G>A (p.Gly119Arg) is a missense variant in exon 5 of FANCL, a gene associated with autosomal recessive Fanconi anemia. PVS1 is not applicable as this is not a null variant.
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCL c.355G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_018062.3 · variants mapped to exon structure
FANCL
NM_018062.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_018062.3:c.355G>A is extremely rare in population databases. In gnomAD v2.1, the total allele frequency is 7.96e-06 (2/251,302 alleles; 0.0008%), and in gnomAD v4.1 the allele frequency is 6.21e-07 (1/1,611,258 alleles; 0.00006%). Both are well below the 0.1% PM2 threshold for generic ACMG/AMP. The variant is absent from gnomAD-Canada. The highest subpopulation frequency is in East Asian (v2.1: 0.0109%, 2/18,394).
gnomAD v2.1: AF=7.96e-06 (2/251302 alleles0 hom)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.104 (well below typical pathogenic thresholds ≥0.5), BayesDel score is -0.400665 (negative, supporting a benign interpretation), and SpliceAI predicts no splicing impact (max delta score = 0.03, below the 0.1 threshold). Three independent in silico tools concordantly predict a benign or non-deleterious effect.
REVEL: 0.104 (not predicted damaging).BayesDel: -0.400665 (predicted benign).SpliceAI: max delta 0.03 (no predicted splice impact).
Assessed · not applied
· 20 not met · 0 not assessed
Pathogenic
PS2
No de novo observation of NM_018062.3:c.355G>A has been reported in any of the seven reviewed publications.
PS3
No functional studies of NM_018062.3:c.355G>A (p.Gly119Arg) were identified.
PS4
No case-control or case-series data for NM_018062.3:c.355G>A have been reported.
PM1
This variant does not lie in a statistically significant mutational hotspot.
PM6
No de novo observation of this variant has been reported.
PP1
No segregation data are available for NM_018062.3:c.355G>A.
PP2
FANCL is associated with Fanconi anemia, an autosomal recessive disorder where loss of function is a known disease mechanism.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No specific phenotypic data are available for individuals harboring NM_018062.3:c.355G>A.
PP5
No reputable source has recently reported NM_018062.3:c.355G>A as pathogenic.
Benign
BA1
The allele frequency of NM_018062.3:c.355G>A is well below the 1% BA1 threshold.
BS1
The allele frequency is well below the 0.3% BS1 threshold for generic ACMG/AMP.
BS2
No homozygous observations of this variant have been reported in gnomAD (v2.1: 0 homozygotes out of 251,302; v4.1: 0 homozygotes out of 1,611,258).
BS3
No functional studies demonstrating a neutral or benign effect of p.Gly119Arg have been identified.
BS4
No segregation data are available for NM_018062.3:c.355G>A.
BP1
FANCL is associated with Fanconi anemia, an autosomal recessive disorder where loss of function is a known disease mechanism.
BP2
NM_018062.3:c.355G>A has not been observed in trans with a known pathogenic FANCL variant in any reviewed source.
BP5
No case has been identified in which NM_018062.3:c.355G>A was observed alongside an alternate molecular basis for disease.
BP6
No reputable source has classified NM_018062.3:c.355G>A as benign or likely benign.
BP7
NM_018062.3:c.355G>A is a missense variant (p.Gly119Arg), not a synonymous or intronic variant.
N/A · 3
PVS1 · PS1 · PM5
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.20633e-07; MAF= 0.00006%, 1/1611258 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23374e-05; MAF= 0.00223%, 1/44768 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95855e-06; MAF= 0.00080%, 2/251302 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,611,258
0 hom
0 hom
East Asian 1 / 44,768 |
0.0022% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0008%
· 2 / 251,302
0 hom · FAF 0.0019%
0 hom · FAF 0.0019%
East Asian 2 / 18,394 |
0.011% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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 = 653483)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.104. BayesDel score = -0.400665.
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