rs1708629

Variant names:

• chr17-17236983-G-A
• rs1708629
• NM_144997.7:c.-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 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 Conflicting classifications of pathogenicity (no stars).

• 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.728
• Publications: 14 publications found

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]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Orphanet, Ambry Genetics, Genomics England PanelApp
• renal carcinoma

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.-299C>T		5_prime_UTR	Exon 1 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.-507C>T		5_prime_UTR	Exon 1 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.-582C>T		5_prime_UTR	Exon 1 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.-299C>T		5_prime_UTR	Exon 1 of 14	ENSP00000285071.4	Q8NFG4-1
	FLCN	ENST00000389169.9	TSL:1	c.-299C>T		5_prime_UTR	Exon 1 of 8	ENSP00000373821.5	Q8NFG4-2
	ENSG00000264187	ENST00000427497.3	TSL:1	n.-299C>T		non_coding_transcript_exon	Exon 1 of 12	ENSP00000394249.3	J3QW42

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Birt-Hogg-Dube syndrome (1)
-	1	-	Colorectal cancer;C1868193:Familial spontaneous pneumothorax;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 (1)
-	-	1	Familial spontaneous pneumothorax (1)
-	-	1	FLCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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;