rs398124524
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1117C>T(p.Gln373Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,778 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
Consequence
NM_144997.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1117C>T | p.Gln373Ter | stop_gained | 10/14 | ENST00000285071.9 | NP_659434.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1117C>T | p.Gln373Ter | stop_gained | 10/14 | 1 | NM_144997.7 | ENSP00000285071 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-362G>A | intron_variant | 3 | ENSP00000464276 | |||||
FLCN | ENST00000577591.1 | n.140C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727174
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2024 | 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 (gnomAD); This variant is associated with the following publications: (PMID: 29357828, 36744932, 22679611) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | FLCN: PVS1, PM2, PS4:Supporting - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2022 | The p.Q373* pathogenic mutation (also known as c.1117C>T), located in coding exon 7 of the FLCN gene, results from a C to T substitution at nucleotide position 1117. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This mutation has been described in a 47-year-old woman with pulmonary cysts, recurrent pneumothoraces, cutaneous fibrofolliculomas, and a family history of multiple affected relatives (Rehman HU. Can. Respir. J. 19(3):193-5). 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. - |
Birt-Hogg-Dube syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2023 | This sequence change creates a premature translational stop signal (p.Gln373*) 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 (BHDS) (PMID: 22679611). ClinVar contains an entry for this variant (Variation ID: 96469). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at