rs1708629

Positions:

• chr17-17236983-G-A
• chr17-17236983-G-C
• chr17-17236983-G-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.-299C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 151,880 control chromosomes in the GnomAD database, including 18,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18612 hom., cov: 31)
  • Exomes 𝑓: 0.58 (8 hom.)
• Consequence: FLCN NM_144997.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.728

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=-0.82).
• BP6: Variant 17-17236983-G-A is Benign according to our data. Variant chr17-17236983-G-A is described in ClinVar as [Benign]. Clinvar id is 322082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17236983-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.-299C>T		5_prime_UTR_variant	1/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.-299C>T		5_prime_UTR_variant	1/14	1	NM_144997.7	P1
FLCN	ENST00000389169.9	c.-299C>T		5_prime_UTR_variant	1/8	1
FLCN	ENST00000417064.1	c.-99C>T		5_prime_UTR_variant	1/4	2
FLCN	ENST00000389171.4	n.206C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68687 AN: 151714 Hom.: 18617 Cov.: 31

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.441

GnomAD4 exome AF: 0.583 AC: 28 AN: 48 Hom.: 8 Cov.: 0 AF XY: 0.533 AC XY: 16 AN XY: 30

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.452 AC: 68681 AN: 151832 Hom.: 18612 Cov.: 31 AF XY: 0.460 AC XY: 34108 AN XY: 74170

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.527

Gnomad4 EAS AF: 0.625

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.732

Gnomad4 NFE AF: 0.560

Gnomad4 OTH AF: 0.436

Alfa AF: 0.494 Hom.: 2511

Bravo AF: 0.427

Asia WGS AF: 0.529 AC: 1835 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	-0.82
CADD	Benign	9.4
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1708629; hg19: chr17-17140297;