rs587782069

Positions:

• chr17-17224041-G-A
• chr17-17224041-G-C
• chr17-17224041-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.499C>T​(p.Gln167Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,518 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FLCN NM_144997.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17224041-G-A is Pathogenic according to our data. Variant chr17-17224041-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 141865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17224041-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.499C>T	p.Gln167Ter	stop_gained	6/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.499C>T	p.Gln167Ter	stop_gained	6/14	1	NM_144997.7	ENSP00000285071	P1
FLCN	ENST00000389169.9	c.499C>T	p.Gln167Ter	stop_gained	6/8	1		ENSP00000373821
FLCN	ENST00000417064.1	c.340C>T	p.Gln114Ter	stop_gained	4/4	2		ENSP00000410410
FLCN	ENST00000480316.1	n.465C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727056

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2023	This sequence change creates a premature translational stop signal (p.Gln167*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 141865). This premature translational stop signal has been observed in individual(s) with clinical features of Birt-Hogg-Dubé syndrome, in at least one of whom it was found de novo (PMID: 23264078, 23784378, 26603437, 27257988, 27652079). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 18, 2016	- -

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

Apr 22, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2022

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; Observed in individuals with BirtHoggDub syndrome in published literature, including one individual with this variant observed de novo with confirmed parentage (Menko 2013, Johannesma 2016, Sattler 2017, Radzikowska 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23784378, 28152038, 27257988, 15852235, 29357828, 28869776, 23264078, 26603437, 34229741, 27652079) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2022

The p.Q167* pathogenic mutation (also known as c.499C>T), located in coding exon 3 of the FLCN gene, results from a C to T substitution at nucleotide position 499. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation has been identified in multiple individuals with Birt-Hogg-Dube syndrome (Menko FH et al. Fam. Cancer, 2013 Sep;12:373-9; Luijten MN et al. Hum. Mol. Genet., 2013 Nov;22:4383-97; Johannesma PC et al. Fam. Cancer, 2016 Apr;15:297-300; Demir M et al. Pediatr Pulmonol, 2016 12;51:E41-E43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.80
GERP RS		5.7
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: rs587782069; hg19: chr17-17127355; COSMIC: COSV104533886; COSMIC: COSV104533886;