rs398124539

Variant names:

• chr17-17221578-G-GCA
• rs398124539
• NM_144997.7:c.828_829dupTG

Variant summary

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

The NM_144997.7(FLCN):​c.828_829dupTG​(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]

ENSG00000264187 (HGNC:):

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 rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.828_829dupTG	p.Ala277ValfsTer17	frameshift_variant	Exon 8 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.828_829dupTG	p.Ala277ValfsTer17	frameshift_variant	Exon 8 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-2526_149-2525dupTG		intron_variant	Intron 4 of 11	1		ENSP00000394249.3

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

Jul 08, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Birt-Hogg-Dube syndrome Pathogenic:1

Jun 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). 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). -

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;