rs139418842

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_144997.7(FLCN):c.113G>T(p.Ser38Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 3.61

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 links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054115772).

BP6

Variant 17-17228025-C-A is Benign according to our data. Variant chr17-17228025-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.113G>T	p.Ser38Ile	missense_variant	4/14	ENST00000285071.9	NP_659434.2	Q8NFG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.113G>T	p.Ser38Ile	missense_variant	4/14	1	NM_144997.7	ENSP00000285071.4		Q8NFG4-1
ENSG00000264187	ENST00000427497.3 linkuse as main transcript	n.113G>T		non_coding_transcript_exon_variant	4/12	1		ENSP00000394249.3		J3QW42

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251242

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000131

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2022

- -

FLCN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 22, 2024

The FLCN c.113G>T variant is predicted to result in the amino acid substitution p.Ser38Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain significance to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/409391/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:Potocki-Lupski syndrome;CN074294:Nonpapillary renal cell carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 03, 2021

- -

Birt-Hogg-Dube syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 07, 2024

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2023

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Birt-Hogg-Dube syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.64

T;T

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.054

T;T

MetaSVM

Uncertain

-0.030

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.27

Sift

Benign

0.44

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;B

Vest4

0.13

MVP

0.30

MPC

0.44

ClinPred

0.088

GERP RS

5.5

Varity_R

0.13

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over