rs878855217

Positions:

• chr17-17223955-TC-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.584del​(p.Gly195GlufsTer28) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.93

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 17-17223955-TC-T is Pathogenic according to our data. Variant chr17-17223955-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 241927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17223955-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.584del	p.Gly195GlufsTer28	frameshift_variant	6/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.584del	p.Gly195GlufsTer28	frameshift_variant	6/14	1	NM_144997.7	P1
FLCN	ENST00000389169.9	c.584del	p.Gly195GlufsTer28	frameshift_variant	6/8	1
FLCN	ENST00000417064.1	c.425del	p.Gly142GlufsTer?	frameshift_variant	4/4	2
FLCN	ENST00000480316.1	n.550del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74364

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

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Gly195Glufs*28) 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 individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 18234728). This variant is also known as c.1036delG and c.1039delG. ClinVar contains an entry for this variant (Variation ID: 241927). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Birt-Hogg-Dube syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 03, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 19, 2020

Frameshift 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 in large population cohorts (Lek 2016); Also known as c.1036delG and c.1039delG; This variant is associated with the following publications: (PMID: 27734835, 29357828, 19562744, 19802896, 21937013, 15852235, 18234728) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.584delG pathogenic mutation, located in coding exon 3 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 584, causing a translational frameshift with a predicted alternate stop codon (p.G195EFS*28). This mutation has been reported in multiple unrelated individuals with a clinical diagnosis of Birt-Hogg-Dube (BHD) syndrome (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun;76:1023-33; Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31; Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). Of note, this alteration is also designated as c.1039delG and c.1036delG in published literature. 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs878855217; hg19: chr17-17127269;