rs3744123

Positions:

chr17-17224156-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144997.7(FLCN):c.397-13G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,569,198 control chromosomes in the GnomAD database, including 1,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 706 hom., cov: 33)

Exomes 𝑓: 0.028 ( 1114 hom. )

Consequence

FLCN
NM_144997.7 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.00600

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 17-17224156-C-T is Benign according to our data. Variant chr17-17224156-C-T is described in ClinVar as [Benign]. Clinvar id is 96485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17224156-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.397-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.397-13G>A	splice_polypyrimidine_tract_variant, intron_variant		1	NM_144997.7	P1	Q8NFG4-1
FLCN	ENST00000389169.9 linkuse as main transcript	c.397-13G>A	splice_polypyrimidine_tract_variant, intron_variant		1			Q8NFG4-2
FLCN	ENST00000417064.1 linkuse as main transcript	c.238-13G>A	splice_polypyrimidine_tract_variant, intron_variant		2
FLCN	ENST00000480316.1 linkuse as main transcript	n.350G>A	non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0662

AC:

10080

AN:

152184

Hom.:

706

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0309

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.0192

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0249

Gnomad OTH

AF:

0.0599

GnomAD3 exomes

AF:

0.0328

AC:

5801

AN:

176948

Hom.:

275

AF XY:

0.0297

AC XY:

2811

AN XY:

94490

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.0260

Gnomad ASJ exome

AF:

0.0336

Gnomad EAS exome

AF:

0.000447

Gnomad SAS exome

AF:

0.0247

Gnomad FIN exome

AF:

0.00319

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0325

GnomAD4 exome

AF:

0.0282

AC:

39982

AN:

1416896

Hom.:

1114

Cov.:

AF XY:

0.0274

AC XY:

19234

AN XY:

700812

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.0269

Gnomad4 ASJ exome

AF:

0.0318

Gnomad4 EAS exome

AF:

0.00847

Gnomad4 SAS exome

AF:

0.0229

Gnomad4 FIN exome

AF:

0.00442

Gnomad4 NFE exome

AF:

0.0248

Gnomad4 OTH exome

AF:

0.0384

GnomAD4 genome

AF:

0.0663

AC:

10096

AN:

152302

Hom.:

706

Cov.:

AF XY:

0.0642

AC XY:

4783

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.179

Gnomad4 AMR

AF:

0.0375

Gnomad4 ASJ

AF:

0.0309

Gnomad4 EAS

AF:

0.00328

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.0249

Gnomad4 OTH

AF:

0.0592

Alfa

AF:

0.0443

Hom.:

Bravo

AF:

0.0737

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	397-13G>A in intron 5 of FLCN: This variant is not expected to have clinical sig nificance because it has been identified in 17.6% (776/4400) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs3744123). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Birt-Hogg-Dube syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2016	Variant summary: The FLCN c.397-13G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 4/5 splice prediction tools predict that this variant abolish or weaken the normal 3' splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant is found in 1915/41366 control chromosomes (107 homozygotes) at a frequency of 0.0462941, which significantly exceeds the estimated maximal expected allele frequency of a pathogenic variant (0.0000013), suggesting this variant is benign. In addition, one clinical laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial spontaneous pneumothorax

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.1

DANN

Benign

0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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