rs786203218
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_144997.7(FLCN):c.469_471delTTC(p.Phe157del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_144997.7 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLCN | ENST00000285071.9 | c.469_471delTTC | p.Phe157del | conservative_inframe_deletion | Exon 6 of 14 | 1 | NM_144997.7 | ENSP00000285071.4 | ||
ENSG00000264187 | ENST00000427497.3 | n.148+3919_148+3921delTTC | intron_variant | Intron 4 of 11 | 1 | ENSP00000394249.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249864Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135290
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461254Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 726886
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
not provided Pathogenic:3
In-frame deletion of one amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: disrupted protein stability, reduced protein expression (Nahorski et al., 2011); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as c.924_926del; This variant is associated with the following publications: (PMID: 22725638, 27229674, 21538689, 22571569, 25655561, 19802896, 22146830, 22446046, 18505456, 27906882, 28724667, 28869776, 29357828, 30360018, 31625278, 31615547, 34048023, 34604083) -
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The frequency of this variant in the general population, 0.000004 (1/249864 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in in individuals with Brit-Hogg-Dube Syndrome (PMIDs: 18505456 (2008), 22146830 (2011), 27906882 (2016), 33313181 (2020), 31258130 (2019), 22571569 (2012), 25655561 (2015), 30360018 (2019), 31615547 (2019)). Published functional study reports that this variant affects the protein stability and is damaging to the protein function (PMID: 21538689 (2011)). Based on the available information, this variant is classified as pathogenic. -
Birt-Hogg-Dube syndrome Pathogenic:3
This variant, c.469_471del, results in the deletion of 1 amino acid(s) of the FLCN protein (p.Phe157del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786203218, gnomAD 0.0009%). This variant has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 18505456, 22146830, 22571569, 27906882, 28724667). It has also been observed to segregate with disease in related individuals. This variant is also known as c.924_926del. ClinVar contains an entry for this variant (Variation ID: 186785). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FLCN function (PMID: 21538689). For these reasons, this variant has been classified as Pathogenic. -
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Birt-Hogg-Dube syndrome 1 Pathogenic:1
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FLCN-related disorder Pathogenic:1
The FLCN c.469_471delTTC variant is predicted to result in an in-frame deletion (p.Phe157del). This variant, which may also be referred to as c.924_926del, has been reported to be causative for primary spontaneous pneumothorax and Birt–Hogg–Dubé syndrome (Ren et al. 2008. PubMed ID: 18505456; Byrne et al. 2012. PubMed ID: 22571569; Radzikowska et al. 2016. PubMed ID: 27906882). A functional study reported that this variant results in instability of the folliculin protein (Nahorski et al. 2011. PubMed ID: 21538689). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic/likely pathogenic in the ClinVar database. This variant is interpreted as pathogenic. -
Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:Potocki-Lupski syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
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Familial spontaneous pneumothorax Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.469_471delTTC pathogenic mutation (also known as p.F157del) is located in coding exon 3 of the FLCN gene. This pathogenic mutation results from an in-frame TTC deletion at nucleotide positions 469 to 471. This results in the in-frame deletion of a phenylalanine at codon 157. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in numerous individuals and families with clinical features of Birt-Hogg-Dube syndrome (Lim D et al. Hum Mutat. 2010 Jan;31(1):E1043-51; Houweling AC et al. British Journal of Cancer 2011;105:1912–1919; Byrne M et al. Australas J Dermatol. 2012 May;53(2):151-4; Shvartsbeyn M et al. J Cutan Pathol. 2012 Jul;39(7):675-9;Radzikowska E et al. Pol. Arch. Med. Wewn., 2016 Nov;126:897-898). This alteration has been shown to segregate with disease in the literature and in two families tested in our laboratory (Bondavalli D et al. Am. J. Med. Genet. 2015 Apr;167A(4):802-4; Ren H et al. Clin Genet. 2008 Aug;74(2):178-83; Ambry internal data). In vivo analyses indicated that this alteration led to a significantly less stable protein when compared to wildtype (p<0.01) (Nahorski M et al. Hum Mutat. 2011 Aug;32(8):921-9). Of note, this alteration has been referred to as c.924_926delTTC in some literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at