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LYFE SCIENCES
Project: HERA
NM_144997.7:c.1333G>A
p.Ala445Thr  ·  FLCN
ACMG/AMP
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Classification rationale
1

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.

clinvar ↗
2

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%.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:19562744 ↗
4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.00.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.203. BayesDel score = -0.459533.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA445
Hotspots ↗