rs1131690838

Positions:

• chr17-17228134-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_144997.7(FLCN):​c.3del​(p.Met1?) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.31

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 14 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 73 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_144997.7 (FLCN) was described as [Likely_pathogenic] in Lovd
• 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]. Clinvar id is 428655.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-17228134-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.3del	p.Met1?	frameshift_variant, start_lost	4/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.3del	p.Met1?	frameshift_variant, start_lost	4/14	1	NM_144997.7	ENSP00000285071	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2018

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. -

Computational scores

Source: dbNSFP v4.3

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: rs1131690838; hg19: chr17-17131448;