Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The ENST00000285071.9(FLCN):c.12C>G(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

FLCN
ENST00000285071.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -0.843

Publications

0 publications found

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]

FLCN Gene-Disease associations (from GenCC):

Birt-Hogg-Dube syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Birt-Hogg-Dube syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
familial spontaneous pneumothorax
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
renal carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in ENST00000285071.9

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28003627).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000285071.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLCN	NM_144997.7	MANE Select	c.12C>G	p.Ile4Met	missense	Exon 4 of 14	NP_659434.2
FLCN	NM_001353229.2		c.12C>G	p.Ile4Met	missense	Exon 5 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.12C>G	p.Ile4Met	missense	Exon 5 of 15	NP_001340159.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.12C>G	p.Ile4Met	missense	Exon 4 of 14	ENSP00000285071.4
FLCN	ENST00000389169.9	TSL:1	c.12C>G	p.Ile4Met	missense	Exon 4 of 8	ENSP00000373821.5
ENSG00000264187	ENST00000427497.3	TSL:1	n.12C>G		non_coding_transcript_exon	Exon 4 of 12	ENSP00000394249.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Birt-Hogg-Dube syndrome (1)

Birt-Hogg-Dube syndrome 1 (1)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

9.9

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.31

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.030

MutationAssessor

Benign

1.8

PhyloP100

-0.84

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.44

Sift

Uncertain

0.0050

Sift4G

Benign

0.10

Polyphen

0.86

Vest4

0.38

MutPred

0.26

Loss of catalytic residue at I4 (P = 0.0225)

MVP

0.26

MPC

1.2

ClinPred

0.91

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.39

gMVP

0.39

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

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17-17228126-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over