NM_144997.7:c.-685T>C

Variant names:

• chr17-17237369-A-G
• rs1736208
• NM_144997.7:c.-685T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144997.7(FLCN):​c.-685T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 152,108 control chromosomes in the GnomAD database, including 46,338 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46338 hom., cov: 32)
• Consequence: FLCN NM_144997.7 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• Publications: 5 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, 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

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.-685T>C		upstream_gene	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.-893T>C		upstream_gene	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.-968T>C		upstream_gene	N/A	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.-685T>C		upstream_gene	N/A	ENSP00000285071.4
	FLCN	ENST00000389169.9	TSL:1	c.-685T>C		upstream_gene	N/A	ENSP00000373821.5
	ENSG00000264187	ENST00000427497.3	TSL:1	n.-685T>C		upstream_gene	N/A	ENSP00000394249.3

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118470 AN: 151990 Hom.: 46317 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.761

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.779 AC: 118550 AN: 152108 Hom.: 46338 Cov.: 32 AF XY: 0.784 AC XY: 58305 AN XY: 74360

African (AFR) AF: 0.762 AC: 31610 AN: 41478

American (AMR) AF: 0.764 AC: 11678 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2659 AN: 3472

East Asian (EAS) AF: 0.849 AC: 4380 AN: 5162

South Asian (SAS) AF: 0.747 AC: 3596 AN: 4814

European-Finnish (FIN) AF: 0.877 AC: 9293 AN: 10600

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52752 AN: 67978

Other (OTH) AF: 0.758 AC: 1600 AN: 2112

Alfa AF: 0.753 Hom.: 3781

Bravo AF: 0.773

Asia WGS AF: 0.807 AC: 2804 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.70
PhyloP100		-0.19
PromoterAI		0.14	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1736208; hg19: chr17-17140683;