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FLCNc.1333G>ABenign
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Variant interpretation report

FLCN c.1333G>A, p.(Ala445Thr)

NM_144997.7:c.1333G>A NP_659434.2:p.(Ala445Thr) View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FLCN

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: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone

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).

BP1Supporting
BP1 · supporting

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.

Recorded classification: Benign

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
4,730 / 1,614,082 alleles

gnomAD v4.1: 4,730 / 1,614,082 alleles. Recorded AF 0.00293046. Recorded homozygote count 16.

gnomAD 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.

Applied · BA1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 3 not met · 16 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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%.

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.

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

Met · 2

BA1 Stand aloneThis 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). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 Middle Eastern AF 0.0135269 (82/6062).
  • gnomAD v4.1 grpmax FAF 0.0111668.
Sources
gnomad_v4 ↗
BP1 SupportingFLCN-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. Details ▾Hide ▴
Evidence considered
  • FLCN loss of function is an established disease mechanism.
  • The FLCN mutation database reported 2 missense variants among 53 unique germline mutations.
Sources
PMID:19562744 ↗pvs1_gene_context

Not met · 3 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • ClinVar shows predominantly likely benign/benign submissions.
  • Population frequency is high in gnomAD.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots did not show a statistically significant hotspot at A445.
  • OncoKB had no variant-specific review.
Sources
hotspots ↗oncokb ↗
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.0025848 (730/282420).
  • gnomAD v4.1 total AF 0.00293046 (4730/1614082).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 16 · no assessment recorded

PS1 No evidence was identified showing that this nucleotide change results in the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Still missing
  • No pathogenic same-amino-acid comparator was identified in the reviewed sources.
PS2 No confirmed de novo occurrence with verified parentage was identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo case data were identified.
PS3 No well-established functional study demonstrating a damaging effect specific to this variant was identified. Details ▾Hide ▴
Evidence considered
  • Reviewed cited literature and available summary sources without finding a variant-specific damaging functional assay.
Still missing
  • No variant-specific validated functional assay result was identified.
Sources
PMID:19116017 ↗PMID:19562744 ↗
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
  • No phase or recessive-case data were identified.
PM5 No evidence was identified for a different pathogenic missense change at the same amino acid residue that would support PM5. Details ▾Hide ▴
Still missing
  • No pathogenic alternate missense variant at codon 445 was identified in the reviewed sources.
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo case data were identified.
PP1 No segregation data were identified to show that this variant tracks with disease in affected family members. Details ▾Hide ▴
Still missing
  • No informative family segregation data were identified.
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. Details ▾Hide ▴
Evidence considered
  • The FLCN mutation database indicates that truncating variants predominate.
Still missing
  • No gene-specific missense-rate framework supporting PP2 was identified.
Sources
PMID:19562744 ↗
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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
Still missing
  • No cited missense-specific calibrated in silico threshold was available.
Sources
spliceai ↗
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. Details ▾Hide ▴
Still missing
  • No case-specific phenotype information was identified.
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. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 reports 3 homozygotes.
  • gnomAD v4.1 reports 16 homozygotes.
Still missing
  • No disease-specific BS2 framework or penetrance-based threshold was identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study demonstrating a benign effect specific to this variant was identified. Details ▾Hide ▴
Evidence considered
  • Reviewed cited literature and available summary sources without finding a variant-specific benign functional assay.
Still missing
  • No variant-specific validated benign functional assay result was identified.
Sources
PMID:19116017 ↗PMID:19562744 ↗
BS4 No family data were identified showing lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No informative nonsegregation data were identified.
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. Details ▾Hide ▴
Still missing
  • No allelic phase data were identified.
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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
Still missing
  • No cited missense-specific calibrated benign prediction threshold was available.
Sources
spliceai ↗
BP5 No evidence was identified showing that this variant occurs in a case with an alternate molecular basis that fully explains the phenotype. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data were identified.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AFLCN loss of function is an established disease mechanism, but this variant is a missense substitution and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site change. Details ▾Hide ▴
Evidence considered
  • Loss of function is supported as a disease mechanism for FLCN.
  • NM_144997.7:c.1333G>A is a missense variant
  • p.(Ala445Thr).
  • The generic PVS1 scaffold states that this variant is outside the default PVS1 null-variant buckets.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis variant is a missense substitution and does not cause a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Ala445Thr).
PP5 N/APP5 was not applied because assertion-based evidence from external classifications is not used as stand-alone support when primary evidence is available. Details ▾Hide ▴
Evidence considered
  • ClinVar assertions were reviewed as supporting context only.
Sources
clinvar ↗
BS1 N/AThis variant exceeds the BS1 threshold of 0.3% in gnomAD, but BA1 already applies because the Middle Eastern population frequency in gnomAD v4.1 is above the 1% benign stand-alone threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 highest subpopulation AF 0.00370882.
  • gnomAD v4.1 Middle Eastern AF 0.0135269.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region without a known function. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Ala445Thr)
  • a missense substitution.
BP6 N/ABP6 was not applied because assertion-based evidence from external classifications is not used as stand-alone support when primary evidence is available. Details ▾Hide ▴
Evidence considered
  • ClinVar assertions were reviewed as supporting context only.
Sources
clinvar ↗
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or intronic. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Ala445Thr).

Identifiers

Gene
FLCN
Transcript
NM_144997.7
Coding (HGVS c.)
NM_144997.7:c.1333G>A
Protein (HGVS p.)
NP_659434.2:p.(Ala445Thr)
GRCh38
chr17:17215284 C>T
GRCh37
chr17:17118598 C>T

Gene diagram

Every interpreted variant in FLCN, mapped onto the exon structure of NM_144997.7. Select a row to find it on the plot.

FLCNNM_144997.7
Fetching transcript structure from UCSC…
gnomAD v4.1 4,730 / 1,614,082 alleles AF 0.00293 · 16 homozygotes · FAF 0.0112
gnomAD v2.1 730 / 282,420 alleles AF 0.00258 · 3 homozygotes · FAF 0.00341

By genetic ancestry

gnomAD v4.1

AF 0.0029 · 4730 / 1,614,082 alleles · 16 hom · FAF 0.011
Middle Eastern82 / 6,062 0.014
South Asian354 / 91,082 0.00395 hom
Remaining individuals201 / 62,508 0.00321 hom
European (non-Finnish)3761 / 1,180,026 0.00327 hom
Admixed American185 / 60,022 0.00312 hom
Ashkenazi Jewish74 / 29,608 0.0025
European (Finnish)43 / 63,956 0.000671 hom
African/African American29 / 75,046 0.00039
East Asian1 / 44,860 2.2e-05
0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.0026 · 730 / 282,420 alleles · 3 hom · FAF 0.0034
European (non-Finnish)478 / 128,882 0.0037
Remaining individuals25 / 7,222 0.00351 hom
South Asian103 / 30,604 0.00341 hom
Ashkenazi Jewish28 / 10,350 0.0027
Admixed American72 / 35,430 0.0021 hom
European (Finnish)17 / 25,062 0.00068
African/African American7 / 24,924 0.00028
0 alternate alleles recorded in 1 other group: East Asian.

Statements

gnomAD 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.

gnomAD 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.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
Still missing
  • No cited missense-specific calibrated in silico threshold was available.
Sources
spliceai ↗
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. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
Still missing
  • No cited missense-specific calibrated benign prediction threshold was available.
Sources
spliceai ↗
BP7 N/ABP7 does not apply because this variant is missense rather than synonymous or intronic. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Ala445Thr).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.203. BayesDel score = -0.459533.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 4,730 / 1,614,082 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record 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= 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 v2.1

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.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53262268, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.