rs1131690826

Positions:

• chr17-17221628-C-T

Variant summary

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

The ENST00000285071.9(FLCN):​c.780G>A​(p.Trp260Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN ENST00000285071.9 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.15

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 17-17221628-C-T is Pathogenic according to our data. Variant chr17-17221628-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.780G>A	p.Trp260Ter	stop_gained, splice_region_variant	8/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.780G>A	p.Trp260Ter	stop_gained, splice_region_variant	8/14	1	NM_144997.7	ENSP00000285071	P1
FLCN	ENST00000389169.9	c.780G>A	p.Trp260Ter	stop_gained, splice_region_variant	8/8	1		ENSP00000373821
FLCN	ENST00000466317.1	n.623G>A		splice_region_variant, non_coding_transcript_exon_variant	2/2	2
FLCN	ENST00000480316.1	n.746G>A		splice_region_variant, non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2021	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This nonsense change has been observed in individual(s) with Birt-Hogg-Dubé syndrome (PMID: 18579543, 22068306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428638). This sequence change creates a premature translational stop signal (p.Trp260*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2023	Variant summary: FLCN c.780G>A (p.Trp260X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 243998 control chromosomes in gnonmAD. To our knowledge, no occurrence of c.780G>A in individuals affected with Birt-Hogg-Dube Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A different nonsense variant, c.779G>A, resulting in the same premature stop codon, was previously reported in a Swiss family affected with Birt-Hogg-Dube Syndrome (Frolich_2008). The following publication has been ascertained in the context of this evaluation (PMID: 18579543). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2014

The p.W260* pathogenic mutation (also known as c.780G>A), located in coding exon 5 of the FLCN gene, results from a G to A substitution at nucleotide position 780. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. A different mutation, c.779G>A, resulting in the same premature stop codon, p.W260*, was previously reported in three members of a Swiss family affected with episodes of spontaneous pneumothorax and cystic lung cysts (Frolich BA et al. Eur Respir J. 2008 Nov;32(5):1316-20). This same alteration was identified in two brothers affected with head and neck fibrofolliculomas, lung cysts, spontaneous pneumothorax and lipoma of the kidney (Sattler EC et al Acta Derm Venereol. 2012 Mar;92(2)). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.43	D
MutationTaster	Benign	1.0	A;D
Vest4		0.94
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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: rs1131690826; hg19: chr17-17124942;