rs1131690838

Variant names:

• chr17-17228134-TC-T
• rs1131690838
• NM_144997.7:c.3delG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_144997.7(FLCN):​c.3delG​(p.Met1IlefsTer54) variant causes a frameshift, start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 frameshift, start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.31
• 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 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 358 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_144997.7 (FLCN) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17228134-TC-T is Pathogenic according to our data. Variant chr17-17228134-TC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428655.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.3delG	p.Met1IlefsTer54	frameshift_variant, start_lost	Exon 4 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.3delG	p.Met1IlefsTer54	frameshift_variant, start_lost	Exon 4 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.3delG		non_coding_transcript_exon_variant	Exon 4 of 12	1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 23, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3delG pathogenic mutation, located in coding exon 1 of the FLCN gene, results from a deletion of one nucleotide at position 3, causing a translational frameshift with a predicted alternate stop codon (p.M1Ifs*52). This pathogenic mutation has been identified in multiple Birt-Hogg-Dube syndrome (BHDS) families with several individuals who have a history of spontaneous pneumothorax and/or multiple characteristic skin lesions, including pathologically confirmed fibrofolliculomas (Bessis D et al. Br J Dermatol. 2006 Nov;155(5):1067-9; Kluger N et al. Br J Dermatol. 2010 Mar;162(3):527-37). Of note, this alteration may be referred to as c.458delG in some literature. 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. -

Nov 21, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate, PM2_Supporting, PP4_Strong The c.3del, located in coding exon 1/14 of the FLCN gene, results from a deletion of one nucleotide at position 3, causing the deletion of the initiation codon (p.Met1?)(PVS1_Moderate). It is not present in the population database gnomAD v2.1.1, non-cancer dataset (PM2_Supporting). Computational tools predict no significant impact on splicing. To our knowledge, functional studies have not been performed for this variant. It has been reported in five families affected with Birt-Hogg-Dubé syndrome (BHDS) (internal data, PMID: 17034545, PMID: 19785621, PMID: 29357828 and internal data) (PP4_Strong). In addition, it has been reported in ClinVar (1x pathogenic) and LOVD (2x pathogenic) databases. VD). . Based on currently available information, c.3del is classified as a pathogenic variant according to ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=10/90	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: rs1131690838; hg19: chr17-17131448;