rs1131690832

chr17-17219018-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.1062+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FLCN NM_144997.7 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.31

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal 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. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-17219018-C-T is Pathogenic according to our data. Variant chr17-17219018-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17219018-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.1062+1G>A		splice_donor_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.1062+1G>A		splice_donor_variant		1	NM_144997.7	P1
FLCN	ENST00000577591.1	n.85+1G>A		splice_donor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 30, 2023	ClinVar contains an entry for this variant (Variation ID: 428646). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 29720200). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the FLCN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in retention of part of intron 9 sequence and introduces a premature termination codon (PMID: 29720200). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2015

The c.1062+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the FLCN gene. Also designated as IVS9+1G>A in published literature, this alteration was seen in a family with nine members affected with Birt-Hogg-Dube syndrome. Clinical findings included fibrofolliculomas, renal tumors, with lung cysts, and pneumothoraces (Schmidt LS et al. Am. J. Hum. Genet. 2005 Jun; 76(6):1023-33). This alteration was also identified in a Japanese male with multiple lung cysts and a personal and family history of pneumothorax whose RNA showed out of frame inclusion of 130 nucleotides of intron 6 (referred to as intron 9) (Furuya M et al. BMC Med Genomics, 2018 May;11:42). In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs1131690832; hg19: chr17-17122332;