rs879255675
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_144997.7(FLCN):c.1286_1287insA(p.His429GlnfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H429H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144997.7 frameshift
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 | UniProt |
---|---|---|---|---|---|---|---|
FLCN | NM_144997.7 | c.1286_1287insA | p.His429GlnfsTer27 | frameshift_variant | 11/14 | ENST00000285071.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.1286_1287insA | p.His429GlnfsTer27 | frameshift_variant | 11/14 | 1 | NM_144997.7 | P1 | |
MPRIP | ENST00000578209.5 | c.*18-1096dup | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461192Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726918
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Birt-Hogg-Dube syndrome Pathogenic:3
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 | Myriad Genetics, Inc. | Feb 08, 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 | Invitae | Feb 16, 2023 | This sequence change creates a premature translational stop signal (p.His429Glnfs*27) 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 (BHD) syndrome (PMID: 18234728). This variant is also known as c.1741insA. ClinVar contains an entry for this variant (Variation ID: 253247). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2017 | The c.1286dupA variant in the FLCN gene has been reported previously in association with Birt-Hogg-Dube syndrome (Toro et al., 2008; Maffe et al., 2011). The duplication causes a frameshift starting with codon Histidine 429, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.His429GlufsX27. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Based on currently available evidence, we consider c.1286dupA to be pathogenic, and its presence consistent with a diagnosis of Birt-Hogg-Dube syndrome. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | The c.1286dupA pathogenic mutation, located in coding exon 8 of the FLCN gene, results from a duplication of A at nucleotide position 1286, causing a translational frameshift with a predicted alternate stop codon (p.H429Qfs*27). This alteration has been observed in individuals with a personal and/or family history that is consistent with FLCN-related disease (Ambry internal data; Toro JR et al. J Med Genet, 2008 Jun;45:321-31). Of note, this alteration is referred to as c.1741insA in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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