rs1555608515
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000285071.9(FLCN):c.997_998del(p.Ser333ArgfsTer56) 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. S333S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
FLCN
ENST00000285071.9 frameshift
ENST00000285071.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.50
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 Pathogenic. Variant got 12 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 17-17219082-TGA-T is Pathogenic according to our data. Variant chr17-17219082-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 529991.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-17219082-TGA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.997_998del | p.Ser333ArgfsTer56 | frameshift_variant | 9/14 | ENST00000285071.9 | NP_659434.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.997_998del | p.Ser333ArgfsTer56 | frameshift_variant | 9/14 | 1 | NM_144997.7 | ENSP00000285071 | P1 | |
FLCN | ENST00000577591.1 | n.20_21del | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Birt-Hogg-Dube syndrome Pathogenic:2
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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2017 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ser333Argfs*56) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with symptoms consistent with Birt–Hogg–Dub_x0001_é syndrome (PMID: 24393238). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). - |
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