rs113938514
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_144997.7(FLCN):c.726A>T(p.Thr242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,614,218 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.028 ( 97 hom., cov: 32)
Exomes 𝑓: 0.022 ( 434 hom. )
Consequence
FLCN
NM_144997.7 synonymous
NM_144997.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -8.62
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 17-17222554-T-A is Benign according to our data. Variant chr17-17222554-T-A is described in ClinVar as [Benign]. Clinvar id is 96489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222554-T-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-8.62 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.726A>T | p.Thr242= | synonymous_variant | 7/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.726A>T | p.Thr242= | synonymous_variant | 7/14 | 1 | NM_144997.7 | P1 | |
FLCN | ENST00000389169.9 | c.726A>T | p.Thr242= | synonymous_variant | 7/8 | 1 | |||
FLCN | ENST00000466317.1 | n.569A>T | non_coding_transcript_exon_variant | 1/2 | 2 | ||||
FLCN | ENST00000480316.1 | n.692A>T | non_coding_transcript_exon_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0283 AC: 4302AN: 152212Hom.: 97 Cov.: 32
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GnomAD3 exomes AF: 0.0196 AC: 4919AN: 251398Hom.: 80 AF XY: 0.0193 AC XY: 2625AN XY: 135910
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GnomAD4 exome AF: 0.0220 AC: 32188AN: 1461888Hom.: 434 Cov.: 31 AF XY: 0.0218 AC XY: 15850AN XY: 727246
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GnomAD4 genome ? AF: 0.0283 AC: 4305AN: 152330Hom.: 97 Cov.: 32 AF XY: 0.0274 AC XY: 2042AN XY: 74500
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ClinVar
Significance: Benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 21, 2013 | Thr242Thr in exon 7 of FLCN: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 5.4% (239/4406) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs113938514). - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 30, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2016 | Variant summary: The c.726A>T (p.Thr242Thr) variant in FLCN affects a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice-tools in Alamut predict no significant effect on splicing, although these predictions have yet to be confirmed by functional studies. This variant is found in 2446/121198 control chromosomes (42 homozygotes) at a frequency of 0.02018, which greatly exceeds maximal expected frequency of a pathogenic allele (0.0000013), strong evidence that this variant is benign. In addition, multiple reputable clinical laboratories have classified this variant as benign. Taken together, this variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 30, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Birt-Hogg-Dube syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Familial spontaneous pneumothorax Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2014 | This alteration is classified as 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at