rs767671406

Positions:

• chr17-17216505-TGAG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_144997.7(FLCN):​c.1177-5_1177-3delCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FLCN NM_144997.7 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 0.166

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]

ENSG00000264187 (HGNC:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 17-17216505-TGAG-T is Pathogenic according to our data. Variant chr17-17216505-TGAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17216505-TGAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1177-5_1177-3delCTC		splice_region_variant, intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1177-5_1177-3delCTC		splice_region_variant, intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*11-5_*11-3delCTC		splice_region_variant, intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-979_*18-977delGGA		intron_variant		3		ENSP00000464276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248662 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134858

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: 0.0000468

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461480 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727060

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:6 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 06, 2021	The c.1177-5_1177-3delCTC variant in FLCN has been reported in at least 2 individuals with Birt-Hogg-Dube syndrome (BHDS) and 6 individuals with suspected BHDS and segregated with clinical features of the disease in 3 affected individuals from 2 families (Kunogi 2010 PMID: 20413710, Kunogi Okura 2013 PMID: 24190151, Johannesma 2014 PMID: 24994497, Furuya 2016 PMID: 27220747, Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369, Liu 2017 PMID: 28558743). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 228691) and has identified in 0.005% (1/21382) of Finnish and 0.002% (2/111570) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 3 nucleotides in the 3' splice region. In vitro minigene splicing assays functional studies support an impact on splicing, through exon 11 skipping, that leads to a truncated or absent protein (Rossing 2017 PMID: 27734835, Bartram 2017 PMID: 28499369). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Birt-Hogg-Dube syndrome. ACMG/AMP Criteria applied: PS4_Strong, PM2_Supporting, PP1, PS3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 21, 2021	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2024	Variant summary: FLCN c.1177-5_1177-3delCTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence via minigene assay confirmed by Sanger sequencing, that the variant results in skipping of exon 11 and fusion of exon 10 (in frame) to exon 12 which generates a frameshift and premature stop codon (p.T393Sfs33*) (e.g. Bartram_2017). The variant allele was found at a frequency of 1.2e-05 in 248662 control chromosomes. c.1177-5_1177-3delCTC has been reported in the literature in multiple heterozygous individuals affected with Birt-Hogg-Dube Syndrome including in families with multiple affected individuals (e.g. KunogiOkura_2013, Bartram_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function showing that FLCN protein levels in the presence of the variant are severely reduced in vitro and in patient tumor samples and peritoneal metastasis (e.g. Batram_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28499369, 24190151). ClinVar contains an entry for this variant (Variation ID: 228691). Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, flagged submission	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20413710]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 27734835, 24190151, 24994497, 31615547, 28499369]. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change falls in intron 10 of the FLCN gene. It does not directly change the encoded amino acid sequence of the FLCN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs767671406, gnomAD 0.005%). This variant has been observed in individuals with Birt–Hogg–Dubé syndrome (PMID: 19802896, 20413710, 24190151, 24994497, 27220747, 27734835). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27734835, 28499369; Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2022	Non-canonical splice site variant demonstrated to result in loss of function (Kunogi et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28558743, 19802896, 27220747, 24190151, 24994497, 27734835, 11100034, 28499369, 29357828, 31625278, 20413710) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 06, 2022	PP1_moderate, PP4, PM2, PS3, PS4_moderate -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 19, 2018

The FLCN c.1177-5_1177-3delCTC variant (rs767671406) is reported in the literature in individuals with Birt-Hogg-Dube syndrome (Bartram 2017, Furuya 2016, Johannesma 2014, Kunogi Okura 2013, Kunogi 2010), and it has been shown to co-segregate with disease (Kunogi Okura 2013). Functional analyses demonstrate that this intronic variant causes exon skipping ultimately leading to a truncated and destabilized protein (Bartram 2017). This variant is reported by multiple laboratories in ClinVar (Variation ID: 228691). It is found in the general population with a low overall allele frequency of 0.001% (3/243776 alleles) in the Genome Aggregation Database. Computational algorithms also predict that the variant has an impact on the nearby canonical splice acceptor (Alamut v.2.10), consistent with functional studies. Based on available information, this variant is considered pathogenic. REFERENCES Bartram MP et al. Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC Med Genet. 2017 May 12;18(1):53. Furuya M et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. Clin Genet. 2016 Nov;90(5):403-412. Johannesma PC et al. Spontaneous pneumothorax as indicator for Birt-Hogg-Dube syndrome in paediatric patients. BMC Pediatr. 2014 Jul 3;14:171. Kunogi Okura M et al. Pneumothorax developing for the first time in a 73-year-old woman diagnosed with Birt-Hogg-Dube syndrome. Intern Med. 2013;52(21):2453-5. Kunogi M et al. Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010 Apr;47(4):281-7. -

FLCN-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

The FLCN c.1177-5_1177-3delCTC variant is predicted to result in an intronic deletion. This variant has been reported in multiple individuals with Birt-Hogg-Dubé syndrome (Lim et al. 2010. PubMed ID: 19802896; Kunogi et al. 2010. PubMed ID: 20413710; Kunogi Okura et al. 2013. PubMed ID: 24190151). In vitro experimental studies have shown that this variant impacts protein function resulting in the skipping of exon 11 leading to premature protein termination (Bartram et al. 2017. PubMed ID: 28499369). This variant is reported in 0.0047% of alleles in individuals of European (Finnish) descent in gnomAD and has interpretations of uncertain, likely pathogenic, and pathogenic listed in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228691/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2022

The c.1177-5_1177-3delCTC intronic pathogenic mutation is located 3 nucleotides before coding exon 8 of the FLCN gene. This variant results from a deletion of 3 nucleotides (CTC) from positions c.1177-5 to c.1177-3. This variant has been reported in multiple unrelated individuals with features of Birt-Hogg-Dube (BHD) syndrome, or symptoms consistent with BHDS (Lim DH et al. Hum Mutat. 2010 Jan;31(1):E1043-51; Okura M et al. Intern. Med. 2013;52(21):2453-5; Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Bartram MP et al. BMC Med. Genet. 2017 May;18:53) and has been found to segregate with disease (Okura M et al. Intern Med. 2013;52(21):2453-5; Ambry Internal Data). In addition, rtPCR and mini-gene splicing assays both indicate that this alteration results in exon skipping and a transcript lacking coding exon 8 (Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Rossing M et al. J. Hum. Genet. 2017 Feb;62(2):151-157; Bartram MP et al. BMC Med. Genet. 2017 May;18(1):53). Internal RNA studies have also demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -43

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

Publications

LitVar

Other links and lift over

dbSNP: rs767671406; hg19: chr17-17119819;