17-17215228-G-C

Position:

• chr17-17215228-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_144997.7(FLCN):​c.1389C>G​(p.Tyr463Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,860 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y463Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FLCN NM_144997.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: -2.67

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]

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-17215228-G-C is Pathogenic according to our data. Variant chr17-17215228-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17215228-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.1389C>G	p.Tyr463Ter	stop_gained	12/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.1389C>G	p.Tyr463Ter	stop_gained	12/14	1	NM_144997.7	P1
MPRIP	ENST00000578209.5	c.*18-2262G>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461860 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727228

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 07, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 07-28-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Tyr463*) 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 (PMID: 12204536, 15852235, 18234728). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3367). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jul 15, 2021	The FLCN c.1389C>G (p.Tyr463Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function (PVS1). This variant is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This variant has been reported in several families with Birt-Hogg-Dubé syndrome (PS4; PMID: 12204536, 15852235, 18234728), including one large family where the mutation co-segregated with disease in six of six affected individuals (PP1; PMID: 12204536). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4, PM2_Supporting, PP1. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	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 (Lek et al., 2016); Also known as c.1844C>G; This variant is associated with the following publications: (PMID: 19802896, 15852235, 18234728, 23784378, 25525159, 25126726, 28869776, 19562744, 29357828, 31008171, 12204536) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2023	PP1_strong, PP4, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 15, 2022	This nonsense variant causes the premature termination of FLCN protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with Birt-Hogg-Dube (BHD) syndrome (PMID: 12204536 (2002), 15852235 (2005), 18234728 (2008), and 23784378 (2013)). Based on the available information, this variant is classified as pathogenic. -

FLCN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The FLCN c.1389C>G variant is predicted to result in premature protein termination (p.Tyr463*). This variant has been reported in individuals with Birt-Hogg-Dube Syndrome (Nickerson et al. 2002. PubMed ID: 12204536; Toro et al. 2008. PubMed ID: 18234728; Pithadia et al. 2019. PubMed ID: 31008171). It is also known in the literature as c.1844C>G. This variant has not been reported in a large population database and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3367/). Nonsense variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial spontaneous pneumothorax Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 04, 2017

Variant summary: The FLCN c.1389C>G (p.Tyr463X) variant results in a premature termination codon, predicted to cause a truncated or absent FLCN protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. One functional study showed increased interaction with the autophagy kinase ULK1 with this variant as well as impaired binding to the GABA(A) receptor-associated protein and higher levels of sequestome 1 (SQSTM1)( Dunlop_FLCN_Autophagy_2014). This variant is absent in 246200 control chromosomes in gnomAD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. This variant was found in multiple patients with Birt-Hogg-Dube syndrome (Schmidt_FLCN_2005). Taken together, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The p.Y463* pathogenic mutation (also known as c.1389C>G), located in coding exon 9 of the FLCN gene, results from a C to G substitution at nucleotide position 1389. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals with Birt-Hogg-Dubé syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76(6):1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45(6):321-31), including one large family where the mutation co-segregated with disease in six of six affected individuals (Nickerson ML et al. Cancer Cell. 2002 Aug;2(2):157-64). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.081	N
MutationTaster	Benign	1.0	A
Vest4		0.91
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs137852929; hg19: chr17-17118542;