rs786203218

Positions:

chr17-17224068-TGAA-T

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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FLCN
NM_144997.7 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 8.69

Variant links:

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]

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain uDENN FLCN/SMCR8-type (size 156) in uniprot entity FLCN_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_144997.7

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_144997.7. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-17224068-TGAA-T is Pathogenic according to our data. Variant chr17-17224068-TGAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17224068-TGAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.469_471delTTC	p.Phe157del	conservative_inframe_deletion	6/14	ENST00000285071.9	NP_659434.2	Q8NFG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.469_471delTTC	p.Phe157del	conservative_inframe_deletion	6/14	1	NM_144997.7	ENSP00000285071.4		Q8NFG4-1
ENSG00000264187	ENST00000427497.3 linkuse as main transcript	n.148+3919_148+3921delTTC		intron_variant		1		ENSP00000394249.3		J3QW42

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249864

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461254

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 01, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2021	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) -

Birt-Hogg-Dube syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
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	Jan 18, 2024	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-Dub√© 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 protein 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. -

Birt-Hogg-Dube syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 05, 2024

- -

FLCN-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Familial spontaneous pneumothorax

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2009

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2022

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over