rs727504645

Positions:

• chr17-17224093-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_144997.7(FLCN):​c.446del​(p.Gly149AlafsTer28) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.37

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17224093-GC-G is Pathogenic according to our data. Variant chr17-17224093-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179123.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.446del	p.Gly149AlafsTer28	frameshift_variant	6/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.446del	p.Gly149AlafsTer28	frameshift_variant	6/14	1	NM_144997.7	ENSP00000285071	P1
FLCN	ENST00000389169.9	c.446del	p.Gly149AlafsTer28	frameshift_variant	6/8	1		ENSP00000373821
FLCN	ENST00000417064.1	c.287del	p.Gly96AlafsTer28	frameshift_variant	4/4	2		ENSP00000410410
FLCN	ENST00000480316.1	n.412del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459610 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 29, 2016

The p.Gly149fs variant in FLCN has been identified by our laboratory in 1 indivi dual with Birt-Hogg-Dube syndrome. It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amin o acid sequence beginning at position 149 and leads to a premature termination c odon 28 amino acids downstream. This alteration is then predicted to lead to a t runcated or absent protein. Frameshift and other truncating variants in FLCN ha ve been associated with Birt-Hogg-Dube syndrome and recurrent spontaneous pneumo thoraces (Nickerson 2002). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly149fs variant is likely p athogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs727504645; hg19: chr17-17127407;