rs398124524

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_144997.7(FLCN):​c.1117C>T​(p.Gln373Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FLCN
NM_144997.7 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.17
Variant links:
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]

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ACMG classification

Classification made for transcript

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 17-17217128-G-A is Pathogenic according to our data. Variant chr17-17217128-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 96469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17217128-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLCNNM_144997.7 linkuse as main transcriptc.1117C>T p.Gln373Ter stop_gained 10/14 ENST00000285071.9 NP_659434.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLCNENST00000285071.9 linkuse as main transcriptc.1117C>T p.Gln373Ter stop_gained 10/141 NM_144997.7 ENSP00000285071 P1Q8NFG4-1
MPRIPENST00000578209.5 linkuse as main transcriptc.*18-362G>A intron_variant 3 ENSP00000464276
FLCNENST00000577591.1 linkuse as main transcriptn.140C>T non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461778
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 08, 2024Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29357828, 36744932, 22679611) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 08, 2013- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2024FLCN: PVS1, PM2, PS4:Supporting -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsOct 06, 2022The p.Q373* pathogenic mutation (also known as c.1117C>T), located in coding exon 7 of the FLCN gene, results from a C to T substitution at nucleotide position 1117. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This mutation has been described in a 47-year-old woman with pulmonary cysts, recurrent pneumothoraces, cutaneous fibrofolliculomas, and a family history of multiple affected relatives (Rehman HU. Can. Respir. J. 19(3):193-5). 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. -
Birt-Hogg-Dube syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2023This sequence change creates a premature translational stop signal (p.Gln373*) 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 (BHDS) (PMID: 22679611). ClinVar contains an entry for this variant (Variation ID: 96469). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
45
DANN
Uncertain
1.0
Eigen
Pathogenic
1.3
Eigen_PC
Pathogenic
1.2
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A
Vest4
0.96
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs398124524; hg19: chr17-17120442; API