chr17-17219138-C-A

Variant names:

• chr17-17219138-C-A
• rs587781952
• NM_144997.7:c.943G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.943G>T​(p.Glu315*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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. E315E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FLCN NM_144997.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.28
• Publications: 4 publications found

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]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 17-17219138-C-A is Pathogenic according to our data. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219138-C-A is described in CliVar as Pathogenic. Clinvar id is 141706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.943G>T	p.Glu315*	stop_gained	Exon 9 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.943G>T	p.Glu315*	stop_gained	Exon 9 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-84G>T		intron_variant	Intron 4 of 11	1		ENSP00000394249.3
FLCN	ENST00000577591.1	n.-35G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000535 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 18, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 14, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E315* pathogenic mutation (also known as c.943G>T) located in coding exon 6 of the FLCN gene, results from a G to T substitution at nucleotide position 943. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This alteration was previously described in an isolated familial pneumothorax cohort (Graham RB et al. Am. J. Respir. Crit. Care Med. 2005; 172:39-44). In addition to the clinical data presented in the literature, sincepremature 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). -

Birt-Hogg-Dube syndrome Pathogenic:1

Aug 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu315*) 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: 15805188). ClinVar contains an entry for this variant (Variation ID: 141706). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.3
Vest4		0.75
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587781952; hg19: chr17-17122452;