rs398124527

Positions:

• chr17-17215311-CA-C

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.1305del​(p.Phe435LeufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.0420

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]

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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 17-17215311-CA-C is Pathogenic according to our data. Variant chr17-17215311-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 96475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17215311-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1305del	p.Phe435LeufsTer33	frameshift_variant	12/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1305del	p.Phe435LeufsTer33	frameshift_variant	12/14	1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-2176del		intron_variant		3		ENSP00000464276

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Phe435Leufs*33) 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: 15852235). This variant is also known as c.1758delT. ClinVar contains an entry for this variant (Variation ID: 96475). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 07, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Mar 02, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FLCN: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2013	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.1305delT pathogenic mutation, located in coding exon 9 of the FLCN gene, results from a deletion of one nucleotide at nucleotide position 1305, causing a translational frameshift with a predicted alternate stop codon (p.P435Lfs*33). This mutation has been described in a patient with Birt–Hogg–Dube syndrome (BHD) who had a personal history of fibrofolliculoma, renal tumor, lung cyst, and pneumothorax, and no family history of BHD (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). 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)		0.0		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: rs398124527; hg19: chr17-17118625;