rs398124539

Positions:

• chr17-17221578-G-GCA

Variant summary

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

The NM_144997.7(FLCN):​c.829_830insTG​(p.Ala277ValfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A277A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.24

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 17-17221578-G-GCA is Pathogenic according to our data. Variant chr17-17221578-G-GCA is described in ClinVar as [Pathogenic]. Clinvar id is 96490.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.829_830insTG	p.Ala277ValfsTer17	frameshift_variant	8/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9	c.829_830insTG	p.Ala277ValfsTer17	frameshift_variant	8/14	1	NM_144997.7	P1
FLCN	ENST00000389169.9	c.829_830insTG	p.Ala277ValfsTer44	frameshift_variant	8/8	1
FLCN	ENST00000466317.1	n.672_673insTG		non_coding_transcript_exon_variant	2/2	2
FLCN	ENST00000480316.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Eurofins Ntd Llc (ga)

Jul 08, 2013

- -

Birt-Hogg-Dube syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 01, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala277Valfs*17) in the FLCN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant has not been reported in the literature in individuals with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 96490). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124539; hg19: chr17-17124892;