chr17-17215228-G-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_144997.7(FLCN):c.1389C>G(p.Tyr463Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y463Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144997.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1389C>G | p.Tyr463Ter | stop_gained | 12/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1389C>G | p.Tyr463Ter | stop_gained | 12/14 | 1 | NM_144997.7 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-2262G>C | intron_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461860Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Birt-Hogg-Dube syndrome Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 07, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic and reported on 07-28-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jul 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Tyr463*) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 12204536, 15852235, 18234728). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3367). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 15, 2021 | The FLCN c.1389C>G (p.Tyr463Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant has been reported in several families with Birt-Hogg-Dubé syndrome (PS4; PMID: 12204536, 15852235, 18234728), including one large family where the mutation co-segregated with disease in six of six affected individuals (PP1; PMID: 12204536). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting, PP1. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as c.1844C>G; This variant is associated with the following publications: (PMID: 19802896, 15852235, 18234728, 23784378, 25525159, 25126726, 28869776, 19562744, 29357828, 31008171, 12204536) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 30, 2023 | PP1_strong, PP4, PM2, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 15, 2022 | This nonsense variant causes the premature termination of FLCN protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with Birt-Hogg-Dube (BHD) syndrome (PMID: 12204536 (2002), 15852235 (2005), 18234728 (2008), and 23784378 (2013)). Based on the available information, this variant is classified as pathogenic. - |
FLCN-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | The FLCN c.1389C>G variant is predicted to result in premature protein termination (p.Tyr463*). This variant has been reported in individuals with Birt-Hogg-Dube Syndrome (Nickerson et al. 2002. PubMed ID: 12204536; Toro et al. 2008. PubMed ID: 18234728; Pithadia et al. 2019. PubMed ID: 31008171). It is also known in the literature as c.1844C>G. This variant has not been reported in a large population database and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3367/). Nonsense variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Familial spontaneous pneumothorax Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 04, 2017 | Variant summary: The FLCN c.1389C>G (p.Tyr463X) variant results in a premature termination codon, predicted to cause a truncated or absent FLCN protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. One functional study showed increased interaction with the autophagy kinase ULK1 with this variant as well as impaired binding to the GABA(A) receptor-associated protein and higher levels of sequestome 1 (SQSTM1)( Dunlop_FLCN_Autophagy_2014). This variant is absent in 246200 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. This variant was found in multiple patients with Birt-Hogg-Dube syndrome (Schmidt_FLCN_2005). Taken together, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2023 | The p.Y463* pathogenic mutation (also known as c.1389C>G), located in coding exon 9 of the FLCN gene, results from a C to G substitution at nucleotide position 1389. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals with Birt-Hogg-Dubé syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76(6):1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45(6):321-31), including one large family where the mutation co-segregated with disease in six of six affected individuals (Nickerson ML et al. Cancer Cell. 2002 Aug;2(2):157-64). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at