17-17215284-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144997.7(FLCN):​c.1333G>A​(p.Ala445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,082 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:23O:1

Conservation

PhyloP100: -0.0320
Variant links:
Genes affected
FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004835129).
BP6
Variant 17-17215284-C-T is Benign according to our data. Variant chr17-17215284-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, Benign=5, Uncertain_significance=2, not_provided=1}. Variant chr17-17215284-C-T is described in Lovd as [Benign]. Variant chr17-17215284-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00244 (372/152276) while in subpopulation AMR AF= 0.00588 (90/15298). AF 95% confidence interval is 0.0049. There are 0 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 372 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLCNNM_144997.7 linkc.1333G>A p.Ala445Thr missense_variant Exon 12 of 14 ENST00000285071.9 NP_659434.2 Q8NFG4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkc.1333G>A p.Ala445Thr missense_variant Exon 12 of 14 1 NM_144997.7 ENSP00000285071.4 Q8NFG4-1
ENSG00000264187ENST00000427497.3 linkn.*167G>A non_coding_transcript_exon_variant Exon 8 of 12 1 ENSP00000394249.3 J3QW42
ENSG00000264187ENST00000427497.3 linkn.*167G>A 3_prime_UTR_variant Exon 8 of 12 1 ENSP00000394249.3 J3QW42
MPRIPENST00000578209.5 linkc.*18-2206C>T intron_variant Intron 5 of 5 3 ENSP00000464276.1 J3QRL2

Frequencies

GnomAD3 genomes
AF:
0.00244
AC:
372
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00589
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.00334
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00264
AC:
662
AN:
251048
Hom.:
3
AF XY:
0.00280
AC XY:
380
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.00202
Gnomad ASJ exome
AF:
0.00268
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00337
Gnomad FIN exome
AF:
0.000648
Gnomad NFE exome
AF:
0.00370
Gnomad OTH exome
AF:
0.00391
GnomAD4 exome
AF:
0.00298
AC:
4358
AN:
1461806
Hom.:
16
Cov.:
34
AF XY:
0.00307
AC XY:
2235
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00212
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00398
Gnomad4 FIN exome
AF:
0.000712
Gnomad4 NFE exome
AF:
0.00318
Gnomad4 OTH exome
AF:
0.00318
GnomAD4 genome
AF:
0.00244
AC:
372
AN:
152276
Hom.:
0
Cov.:
32
AF XY:
0.00234
AC XY:
174
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00588
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00228
Gnomad4 FIN
AF:
0.000471
Gnomad4 NFE
AF:
0.00334
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00308
Hom.:
4
Bravo
AF:
0.00244
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00256
AC:
22
ExAC
AF:
0.00270
AC:
328
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00387
EpiControl
AF:
0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:23Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:9
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 21, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22703879, 20522427, 21937013, 24728327, 19116017, 12843323, 29357828) -

Aug 30, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: research

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FLCN: BP4, BS2 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Uncertain:1Benign:6
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 18, 2016
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 21, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 06, 2023
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

not specified Benign:5Other:1
Nov 10, 2021
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 13, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 06, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ala445Thr in exon 12 of FLCN: This variant is not expected to have clinical si gnificance because it has been identified in 0.37% (246/66324) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs41419545). Additionally, 47 species including 27 mammals have a threon ine (Thr) at this position. -

Dec 03, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FLCN c.1333G>A (p.Ala445Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 251048 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency greatly exceeds the estimated maximal expected allele frequency for a pathogenic variant in FLCN causing Birt-Hogg-Dube Syndrome phenotype (1.3e-06), strongly suggesting that the variant is benign. c.1333G>A has been reported in the literature in individuals affected with Birt-Hogg-Dube Syndrome (Kahnoski_2003), without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Birt-Hogg-Dube Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, 10 classify as likely benign/benign while 2 classify as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2
Oct 30, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aug 04, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Carcinoma of colon Pathogenic:1
Jul 01, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Familial spontaneous pneumothorax Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.11
DANN
Benign
0.75
DEOGEN2
Benign
0.31
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.0048
T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
-1.0
N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.19
N
REVEL
Benign
0.20
Sift
Benign
0.87
T
Sift4G
Benign
0.55
T
Polyphen
0.0
B
Vest4
0.20
MVP
0.19
MPC
0.36
ClinPred
0.0014
T
GERP RS
-7.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.024
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41419545; hg19: chr17-17118598; COSMIC: COSV53262268; COSMIC: COSV53262268; API