rs1708629

Variant names:

• chr17-17236983-G-A
• rs1708629
• ENST00000427497.3:n.-299C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17236983-G-A
• chr17-17236983-G-C
• chr17-17236983-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000427497.3(ENSG00000264187):​n.-299C>T variant causes a non coding transcript exon 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.45 (18612 hom., cov: 31)
  • Exomes 𝑓: 0.58 (8 hom.)
• Consequence: ENSG00000264187 ENST00000427497.3 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.728
• Publications: 14 publications found

Genes affected

ENSG00000264187 (HGNC:):

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 Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 322082.
• 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 rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.-299C>T		5_prime_UTR_variant	Exon 1 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000264187	ENST00000427497.3	n.-299C>T		non_coding_transcript_exon_variant	Exon 1 of 12	1		ENSP00000394249.3
FLCN	ENST00000285071.9	c.-299C>T		5_prime_UTR_variant	Exon 1 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.-299C>T		5_prime_UTR_variant	Exon 1 of 12	1		ENSP00000394249.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.587 AC: 27 AN: 46

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.150 AC: 6214 AN: 41390

American (AMR) AF: 0.528 AC: 8049 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1827 AN: 3470

East Asian (EAS) AF: 0.625 AC: 3215 AN: 5142

South Asian (SAS) AF: 0.409 AC: 1970 AN: 4812

European-Finnish (FIN) AF: 0.732 AC: 7721 AN: 10550

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38033 AN: 67906

Other (OTH) AF: 0.436 AC: 919 AN: 2108

Alfa AF: 0.481 Hom.: 2525

Bravo AF: 0.427

Asia WGS AF: 0.529 AC: 1835 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Colorectal cancer;C1868193:Familial spontaneous pneumothorax;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 Uncertain:1

May 28, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLCN-related disorder Benign:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial spontaneous pneumothorax Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Birt-Hogg-Dube syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.73
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1708629; hg19: chr17-17140297;