chr17-17216505-TGAG-T

Variant names:

• chr17-17216505-TGAG-T
• rs767671406
• NM_144997.7:c.1177-5_1177-3delCTC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BS2_Supporting

The NM_144997.7(FLCN):​c.1177-5_1177-3delCTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000273659: rtPCR and mini-gene splicing assays both indicate that this alteration results in exon skipping and a transcript lacking coding exon 8 (Kunogi M et al. J. Med. Genet. 2010 Apr" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FLCN NM_144997.7 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:1
• Conservation: PhyloP100: 0.166
• Publications: 1 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]

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000273659: rtPCR and mini-gene splicing assays both indicate that this alteration results in exon skipping and a transcript lacking coding exon 8 (Kunogi M et al. J. Med. Genet. 2010 Apr; 47(4):281-7; Rossing M et al. J. Hum. Genet. 2017 Feb;62(2):151-157; Bartram MP et al. BMC Med. Genet. 2017 May;18(1):53). Internal RNA studies have also demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV001157399: Functional analyses demonstrate that this intronic variant causes exon skipping ultimately leading to a truncated and destabilized protein (Bartram 2017). REFERENCES Bartram MP et al. Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer. BMC Med Genet. 2017 May 12;18(1):53.; SCV000271788: "In vitro minigene splicing assays functional studies support an impact on splicing, through exon 11 skipping, that leads to a truncated or absent protein." PMID:27734835, PMID:28499369; SCV000632828: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27734835, 28499369; internal data).; SCV004188030: Functional studies indicate this variant impacts protein function [PMID: 20413710].; SCV004813407: At least one publication reports experimental evidence evaluating an impact on protein function showing that FLCN protein levels in the presence of the variant are severely reduced in vitro and in patient tumor samples and peritoneal metastasis (e.g. Batram_2017). PMID: 28499369, 24190151; SCV000321661: Non-canonical splice site variant demonstrated to result in loss of function (Kunogi et al., 2010); SCV005623364: "In addition, experimental studies have shown that this variant causes exon 11 skipping which results in a truncated FLCN protein with reduced stability (PMIDs: 28499369 (2017) and 27734835 (2017))."; SCV005352118: "In vitro experimental studies have shown that this variant impacts protein function resulting in the skipping of exon 11 leading to premature protein termination (Bartram et al. 2017. PubMed ID: 28499369)."
• PP5: Variant 17-17216505-TGAG-T is Pathogenic according to our data. Variant chr17-17216505-TGAG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.1177-5_1177-3delCTC		splice_region intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.1231-5_1231-3delCTC		splice_region intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.1177-5_1177-3delCTC		splice_region intron	N/A	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1177-5_1177-3delCTC		splice_region intron	N/A	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*11-5_*11-3delCTC		splice_region intron	N/A	ENSP00000394249.3	J3QW42
	FLCN	ENST00000962729.1		c.1282-5_1282-3delCTC		splice_region intron	N/A	ENSP00000632788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248662 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461480 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111904

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	1	-	Birt-Hogg-Dube syndrome (7)
4	-	-	not provided (4)
1	-	-	FLCN-related disorder (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not specified (1)
1	-	-	Pneumothorax - familial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -43

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

Other links and lift over

dbSNP: rs767671406; hg19: chr17-17119819;