17-17213858-T-C

Position:

• chr17-17213858-T-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.1539-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.74

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]

ENSG00000264187 (HGNC:):

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17213858-T-C is Pathogenic according to our data. Variant chr17-17213858-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 241920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17213858-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1539-2A>G		splice_acceptor_variant, intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1539-2A>G		splice_acceptor_variant, intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*372+1127A>G		intron_variant		1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-3632T>C		intron_variant		3		ENSP00000464276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2023

Canonical splice site variant predicted to result in an out-of-frame loss of the last exon in a gene for which loss of function is a known mechanism of disease; Identified in patients with Birt-Hogg-Dube syndrome referred for genetic testing at GeneDx and in published literature (PMID: 25302759); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25537564, 27652079, 37370942, 25302759) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.1539-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 11 in the FLCN gene. This alteration occurs at the 3' terminus of the FLCN gene and is not expected to trigger nonsense-mediated mRNA decay. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been observed individuals with a personal and/or family history that is consistent with FLCN-related disease (Johannesma PC et al. Springerplus, 2016 Sep;5:1506; Park HJ et al. Diagnostics (Basel). 2023 Jun;13(12); Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Birt-Hogg-Dube syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change affects an acceptor splice site in intron 13 of the FLCN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 25302759, 25537564, 27652079). ClinVar contains an entry for this variant (Variation ID: 241920). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: -7
DS_AL_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878855214; hg19: chr17-17117172;