rs3744123

Positions:

• chr17-17224156-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144997.7(FLCN):​c.397-13G>A variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.00600

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]

ENSG00000264187 (HGNC:):

ACMG classification

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	Protein	UniProt
FLCN	NM_144997.7	c.397-13G>A		intron_variant		ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.397-13G>A		intron_variant		1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+3834G>A		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10080 AN: 152184 Hom.: 706 Cov.: 33

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

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.: 31 AF XY: 0.0274 AC XY: 19234 AN XY: 700812

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.: 33 AF XY: 0.0642 AC XY: 4783 AN XY: 74482

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.: 60

Bravo AF: 0.0737

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Jun 18, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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	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. -
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

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

Other links and lift over

dbSNP: rs3744123; hg19: chr17-17127470;