rs879255678
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1429C>T(p.Arg477*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,988 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
FLCN
NM_144997.7 stop_gained
NM_144997.7 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.18
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-17215188-G-A is Pathogenic according to our data. Variant chr17-17215188-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17215188-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FLCN | ENST00000285071.9 | c.1429C>T | p.Arg477* | stop_gained | 12/14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
| ENSG00000264187 | ENST00000427497.3 | n.*263C>T | non_coding_transcript_exon_variant | 8/12 | 1 | ENSP00000394249.3 | ||||
| ENSG00000264187 | ENST00000427497.3 | n.*263C>T | 3_prime_UTR_variant | 8/12 | 1 | ENSP00000394249.3 | ||||
| MPRIP | ENST00000578209.5 | c.*18-2302G>A | intron_variant | 3 | ENSP00000464276.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461808Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727198
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GnomAD4 genome 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 05, 2024 | PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2015 | The R477X nonsense variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dube Syndrome (BHD) (Furuya et al., 2015; Schmidt et al., 2005). It has also been reported in a family with pneumothorax and blebs (Graham et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 23, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 18, 2023 | The FLCN c.1429C>T (p.Arg477*) variant causes the premature termination of FLCN protein synthesis. This variant has been reported in the published literature in affected individuals and families with Burt-Hogg-Dube Syndrome (BHD) (PMIDs: 15805188 (2005), 15852235 (2005), 20618353 (2011), 24393238 (2014), 25594584 (2015), 28558743 (2017), 30360018 (2019), 32782288 (2020), 34148334 (2021), 34703430 (2021), and 35639097 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Birt-Hogg-Dube syndrome Pathogenic:4
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg477*) 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: 15852235, 19457309, 20618353, 24393238, 28558743). This variant is also known as c.1884C>T. ClinVar contains an entry for this variant (Variation ID: 253251). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine | Jul 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 02, 2016 | - - |
Birt-Hogg-Dube syndrome;C0699790:Carcinoma of colon;C1868193:Familial spontaneous pneumothorax;C2931246:Potocki-Lupski syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Colorectal cancer;C1868193:Familial spontaneous pneumothorax;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 15, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2024 | The p.R477* pathogenic mutation (also known as c.1429C>T), located in coding exon 9 of the FLCN gene, results from a C to T substitution at nucleotide position 1429. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in the literature in multiple individuals with clinical diagnoses of Birt-Hogg-Dubé (BHD) syndrome and primary spontaneous pneumothorax. Clinical findings reported in association with this mutation include BHD-associated cutaneous features, lung cysts, pneumothoraces, and renal cell carcinoma (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33; Graham RB et al. Am. J. Respir. Crit. Care Med. 2005 Jul; 172(1):39-44; Fuertes I et al. Actas Dermosifiliogr. 2009 Apr; 100(3):227-30; Maffé A et al. Clin. Genet. 2011 Apr; 79(4):345-54; Furuya M et al. Cancer Sci. 2015 Mar; 106(3):315-23; Liu Y et al. Orphanet J Rare Dis. 2017 May 30;12(1):104). Of note, this alteration is also designated as c.1884C>T, p.477R>X, and R477X in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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