rs1736209

Positions:

• chr17-17237171-C-G
• chr17-17237171-C-T

Variant summary

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

The ENST00000417064.1(FLCN):​c.-287G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 152,062 control chromosomes in the GnomAD database, including 40,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40717 hom., cov: 31)
  • Exomes 𝑓: 0.80 (19 hom.)
• Consequence: FLCN ENST00000417064.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.118

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-17237171-C-G is Benign according to our data. Variant chr17-17237171-C-G is described in ClinVar as [Benign]. Clinvar id is 322087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17237171-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7			upstream_gene_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000417064.1	c.-287G>C		5_prime_UTR_variant	1/4	2
FLCN	ENST00000389171.4	n.18G>C		non_coding_transcript_exon_variant	1/5	2
FLCN	ENST00000285071.9			upstream_gene_variant		1	NM_144997.7	P1
FLCN	ENST00000389169.9			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110524 AN: 151888 Hom.: 40709 Cov.: 31

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.738

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.846

Gnomad SAS AF: 0.725

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.714

GnomAD4 exome AF: 0.804 AC: 45 AN: 56 Hom.: 19 Cov.: 0 AF XY: 0.781 AC XY: 25 AN XY: 32

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.810

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.727 AC: 110573 AN: 152006 Hom.: 40717 Cov.: 31 AF XY: 0.733 AC XY: 54434 AN XY: 74294

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.737

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.846

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.711

Alfa AF: 0.746 Hom.: 5256

Bravo AF: 0.717

Asia WGS AF: 0.779 AC: 2706 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial spontaneous pneumothorax Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Birt-Hogg-Dube syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.67

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: rs1736209; hg19: chr17-17140485;