rs398124527
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1305del(p.Phe435LeufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F435F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
FLCN
NM_144997.7 frameshift
NM_144997.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0420
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 17-17215311-CA-C is Pathogenic according to our data. Variant chr17-17215311-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 96475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17215311-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1305del | p.Phe435LeufsTer33 | frameshift_variant | 12/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1305del | p.Phe435LeufsTer33 | frameshift_variant | 12/14 | 1 | NM_144997.7 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-2176del | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Birt-Hogg-Dube syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Mar 02, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Phe435Leufs*33) 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). This variant is also known as c.1758delT. ClinVar contains an entry for this variant (Variation ID: 96475). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 22, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | FLCN: PVS1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2024 | The c.1305delT pathogenic mutation, located in coding exon 9 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1305, causing a translational frameshift with a predicted alternate stop codon (p.P435Lfs*33). This mutation has been described in a patient with Birt–Hogg–Dube syndrome (BHD) who had a personal history of fibrofolliculoma, renal tumor, lung cyst, and pneumothorax, and no family history of BHD (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). 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
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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