rs113938514

Positions:

• chr17-17222554-T-A
• chr17-17222554-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144997.7(FLCN):​c.726A>T​(p.Thr242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,614,218 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (97 hom., cov: 32)
  • Exomes 𝑓: 0.022 (434 hom.)
• Consequence: FLCN NM_144997.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -8.62

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-17222554-T-A is Benign according to our data. Variant chr17-17222554-T-A is described in ClinVar as [Benign]. Clinvar id is 96489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17222554-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.726A>T	p.Thr242=	synonymous_variant	7/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.726A>T	p.Thr242=	synonymous_variant	7/14	1	NM_144997.7	ENSP00000285071	P1
FLCN	ENST00000389169.9	c.726A>T	p.Thr242=	synonymous_variant	7/8	1		ENSP00000373821
FLCN	ENST00000466317.1	n.569A>T		non_coding_transcript_exon_variant	1/2	2
FLCN	ENST00000480316.1	n.692A>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4302 AN: 152212 Hom.: 97 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0188

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0196 AC: 4919 AN: 251398 Hom.: 80 AF XY: 0.0193 AC XY: 2625 AN XY: 135910

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00919

Gnomad ASJ exome AF: 0.0304

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0237

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0220 AC: 32188 AN: 1461888 Hom.: 434 Cov.: 31 AF XY: 0.0218 AC XY: 15850 AN XY: 727246

Gnomad4 AFR exome AF: 0.0562

Gnomad4 AMR exome AF: 0.00977

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.00806

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.00425

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.0283 AC: 4305 AN: 152330 Hom.: 97 Cov.: 32 AF XY: 0.0274 AC XY: 2042 AN XY: 74500

Gnomad4 AFR AF: 0.0547

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0170 Hom.: 7

Bravo AF: 0.0295

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr242Thr in exon 7 of FLCN: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 5.4% (239/4406) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs113938514). -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The c.726A>T (p.Thr242Thr) variant in FLCN affects a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice-tools in Alamut predict no significant effect on splicing, although these predictions have yet to be confirmed by functional studies. This variant is found in 2446/121198 control chromosomes (42 homozygotes) at a frequency of 0.02018, which greatly exceeds maximal expected frequency of a pathogenic allele (0.0000013), strong evidence that this variant is benign. In addition, multiple reputable clinical laboratories have classified this variant as benign. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial spontaneous pneumothorax Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2014

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	-0.86
CADD	Benign	0.14
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs113938514; hg19: chr17-17125868;