The FLCN c.1333G>A (p.Ala445Thr) variant has been reported in ClinVar predominantly as likely benign or benign, with only a single uncertain significance submission.1 This variant is common in population databases, including gnomAD v2.1 with a total allele frequency of 0.25848% and a highest observed subpopulation frequency of 0.37088%, and gnomAD v4.1 with a total allele frequency of 0.29305% and a Middle Eastern population frequency of 1.35269%, which exceeds the usual benign stand-alone threshold of 1%.2 FLCN-related disease is primarily associated with loss-of-function variants, and the reviewed FLCN mutation database reported only 2 missense variants among 53 unique germline mutations, which supports a benign interpretation for this missense change.3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.00.4
Final classification
Benign
BA1BP1
FLCN
c.1333G>A
p.Ala445Thr
This variant
The FLCN c.1333G>A (p.Ala445Thr) variant has been reported in ClinVar predominantly as likely benign or benign, with only a single uncertain significance submission.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BP1 supporting; combination = 1 stand-alone benign + 1 supporting benign, which maps to Benign.
Classification rationale
BA1BP1
Benign
FLCN c.1333G>A
BA1 + BP1
→
Benign
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.
Gene diagram
· NM_144997.7 · variants mapped to exon structure
FLCN
NM_144997.7
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 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
BA1
stand-alone
Benign
This variant exceeds the benign stand-alone population threshold of 1% in gnomAD v4.1, where the highest observed subpopulation frequency is 1.35269% in the Middle Eastern population (82/6062 alleles).
gnomAD v4.1 Middle Eastern AF 0.0135269 (82/6062).gnomAD v4.1 grpmax FAF 0.0111668.
BP1
supporting
Benign
FLCN-related disease is primarily associated with loss-of-function variants, and the reviewed FLCN mutation database reported only 2 missense variants among 53 unique germline mutations, making a missense mechanism less likely for this gene.
FLCN loss of function is an established disease mechanism.The FLCN mutation database reported 2 missense variants among 53 unique germline mutations.
Assessed · not applied
· 3 not met · 16 not assessed
Pathogenic
PS1
No evidence was identified showing that this nucleotide change results in the same amino acid change as a previously established pathogenic variant.
PS2
No confirmed de novo occurrence with verified parentage was identified for this variant.
PS3
No well-established functional study demonstrating a damaging effect specific to this variant was identified.
PS4
This variant has been reported in ClinVar, but no evidence was identified showing statistically increased prevalence in affected individuals compared with controls; its relatively high population frequency also argues against case enrichment.
PM1
This variant does not lie in a statistically significant hotspot, and no evidence was identified placing Ala445 in a well-established critical functional domain without benign variation.
PM2
Population frequency is above the PM2 rarity threshold of 0.1%: gnomAD v2.1 total AF is 0.25848% and gnomAD v4.1 total AF is 0.29305%, so this variant is not rare enough for PM2.
PM3
No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM5
No evidence was identified for a different pathogenic missense change at the same amino acid residue that would support PM5.
PM6
No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1
No segregation data were identified to show that this variant tracks with disease in affected family members.
PP2
Available evidence does not establish that FLCN is a gene in which pathogenic missense variation is a common disease mechanism and benign missense variation is uncommon.
PP3
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, and no cited missense-specific calibrated prediction framework was available in the reviewed sources to support PP3.
PP4
No phenotype or family history data were provided that would establish a highly specific clinical presentation attributable to a single genetic etiology for this variant.
Benign
BS2
This variant is observed in population databases, including homozygotes, but available evidence is insufficient to determine whether observation in apparently unaffected individuals can be used as a stand-alone BS2 argument for FLCN-associated disease.
BS3
No well-established functional study demonstrating a benign effect specific to this variant was identified.
BS4
No family data were identified showing lack of segregation with disease.
BP2
No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP4
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, but the reviewed sources did not provide a cited missense-specific calibrated framework sufficient to apply BP4 for protein effect.
BP5
No evidence was identified showing that this variant occurs in a case with an alternate molecular basis that fully explains the phenotype.
N/A · 7
PVS1 · PM4 · PP5 · BS1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00293046; MAF= 0.29305%, 4730/1614082 alleles, homozygotes = 16) and has highest observed frequency in the Middle Eastern population (AF= 0.0135269; MAF= 1.35269%, 82/6062 alleles, homozygotes = 0); grpmax FAF= 0.0111668.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0025848; MAF= 0.25848%, 730/282420 alleles, homozygotes = 3) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00370882; MAF= 0.37088%, 478/128882 alleles, homozygotes = 0); grpmax FAF= 0.00340865.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.29%
· 4730 / 1,614,082
16 hom · FAF 1.1%
16 hom · FAF 1.1%
Middle Eastern 82 / 6,062 |
1.4% |
South Asian 354 / 91,082 |
0.39% 5 hom |
Remaining individuals 201 / 62,508 |
0.32% 1 hom |
European (non-Finnish) 3761 / 1,180,026 |
0.32% 7 hom |
Admixed American 185 / 60,022 |
0.31% 2 hom |
Ashkenazi Jewish 74 / 29,608 |
0.25% |
European (Finnish) 43 / 63,956 |
0.067% 1 hom |
African/African American 29 / 75,046 |
0.039% |
East Asian 1 / 44,860 |
0.0022% |
+ 1 not observed (Amish)
gnomAD v2.1
0.26%
· 730 / 282,420
3 hom · FAF 0.34%
3 hom · FAF 0.34%
European (non-Finnish) 478 / 128,882 |
0.37% |
Remaining individuals 25 / 7,222 |
0.35% 1 hom |
South Asian 103 / 30,604 |
0.34% 1 hom |
Ashkenazi Jewish 28 / 10,350 |
0.27% |
Admixed American 72 / 35,430 |
0.2% 1 hom |
European (Finnish) 17 / 25,062 |
0.068% |
African/African American 7 / 24,924 |
0.028% |
+ 1 not observed (East Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (18 clinical laboratories) and as Benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.203. BayesDel score = -0.459533.
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: FLCN, a GTPase activating protein, is altered in various cancer types, including uterine sarcoma, colorectal cancer and bone cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53262268, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
The folliculin mutation database: an online database of mutations associated wit
Found
Structured finding pending for this record — see source link.
Applied to
→BP1
supporting
Sources & reference links