rs886037608

Variant names:

• chr17-17214986-TCATC-T
• rs886037608
• NM_144997.7:c.1533_1536delGATG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_144997.7(FLCN):​c.1533_1536delGATG​(p.Trp511fs) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.47

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:):

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-17214986-TCATC-T is Pathogenic according to our data. Variant chr17-17214986-TCATC-T is described in ClinVar as [Pathogenic]. Clinvar id is 3372.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-17214986-TCATC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1533_1536delGATG	p.Trp511fs	frameshift_variant, splice_region_variant	Exon 13 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1533_1536delGATG	p.Trp511fs	frameshift_variant, splice_region_variant	Exon 13 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.*367_*370delGATG		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 12	1		ENSP00000394249.3
ENSG00000264187	ENST00000427497.3	n.*367_*370delGATG		3_prime_UTR_variant	Exon 9 of 12	1		ENSP00000394249.3
MPRIP	ENST00000578209.5	c.*18-2501_*18-2498delTCCA		intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461598 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:2

Jul 01, 2023

Division of Respiratory Medicine of Juntendo University, Juntendo University Faculty of Medicine and Graduate School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp511*) in the FLCN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 69 amino acid(s) of the FLCN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of FLCN-related condition (PMID: 17496196, 20413710, 22441547). ClinVar contains an entry for this variant (Variation ID: 3372). This variant disrupts a region of the FLCN protein in which other variant(s) (p.Arg527*) have been determined to be pathogenic (PMID: 15852235, 17028174). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial spontaneous pneumothorax Pathogenic:1

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs886037608; hg19: chr17-17118300;