rs1131690840

Positions:

• chr17-17222662-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_144997.7(FLCN):​c.619-1G>A variant causes a splice acceptor change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.09

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 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.9, offset of 1, new splice context is: ccttccctttgcatttcaAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-17222662-C-T is Pathogenic according to our data. Variant chr17-17222662-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222662-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.619-1G>A		splice_acceptor_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.619-1G>A		splice_acceptor_variant		1	NM_144997.7	P1
FLCN	ENST00000389169.9	c.619-1G>A		splice_acceptor_variant		1
FLCN	ENST00000466317.1	n.461G>A		non_coding_transcript_exon_variant	1/2	2
FLCN	ENST00000480316.1	n.585-1G>A		splice_acceptor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Birt-Hogg-Dube syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 03, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 428657). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 17611575, 27652079). This sequence change affects an acceptor splice site in intron 6 of the FLCN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2020	Variant summary: FLCN c.619-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 3'- acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251398 control chromosomes. c.619-1G>A has been reported in the literature in multiple individuals affected with Birt-Hogg-Dube Syndrome (examples- Leter_2008, Houweling_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

FLCN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2023

The FLCN c.619-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with Birt-Hogg-Dube syndrome (Table 1, Referred to as c.1074-1G>A, Leter et al. 2008. PubMed ID: 17611575; Tables S4 and S7, Hartman et al. 2020. PubMed ID: 32782288; Table 2, Houweling et al. 2011. PubMed ID: 22146830; Table 2, Johannesma et al. 2016. PubMed ID: 27652079). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/428657/). Variants that disrupt the consensus splice acceptor site in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2018

The c.619-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 4 of the FLCN gene. This alteration, referred to as c.1074-1G>A, was previously identified in two unrelated families with Birt-Hogg-Dube syndrome (Leter EM et al. J. Invest. Dermatol. 2008 Jan;128(1):45-9). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131690840; hg19: chr17-17125976; COSMIC: COSV53257202; COSMIC: COSV53257202;