chr17-17216394-T-TG

Variant names:

• chr17-17216394-T-TG
• rs80338682
• NM_144997.7:c.1285dupC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_144997.7(FLCN):​c.1285dupC​(p.His429ProfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,612,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001338245: At least one publication reports this variant has an impact on protein function (Hoshika_2016)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H429H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:33 O:2
• Conservation: PhyloP100: 7.28
• Publications: 106 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 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001338245: At least one publication reports this variant has an impact on protein function (Hoshika_2016).; SCV000329354: Published functional studies demonstrate a damaging effect: inactivates gene expression, disrupts protein stability, inhibits tumor suppression, and down-regulates multiple genes involved in TGF-beta signaling (Hong et al., 2010a; Hong et al., 2010b; Nahorski et al., 2011); SCV004218922: Functional studies found that this variant significantly impaired FLCN protein stability and function (PMIDs: 21538689 (2011) and 27905298 (2016)).
• PP5: Variant 17-17216394-T-TG is Pathogenic according to our data. Variant chr17-17216394-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 3363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 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.1285dupC	p.His429ProfsTer27	frameshift	Exon 11 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1339dupC	p.His447ProfsTer27	frameshift	Exon 13 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.1285dupC	p.His429ProfsTer27	frameshift	Exon 12 of 15	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.1285dupC	p.His429ProfsTer27	frameshift	Exon 11 of 14	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*119dupC		non_coding_transcript_exon	Exon 7 of 12	ENSP00000394249.3	J3QW42
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*119dupC		3_prime_UTR	Exon 7 of 12	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151768 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000114 AC: 28 AN: 245324 AF XY: 0.0000375

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000712 AC: 104 AN: 1460472 Hom.: 0 Cov.: 31 AF XY: 0.0000771 AC XY: 56 AN XY: 726548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86186

European-Finnish (FIN) AF: 0.000907 AC: 48 AN: 52922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111418

Other (OTH) AF: 0.0000332 AC: 2 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74252

African (AFR) AF: 0.0000483 AC: 2 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000347 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Birt-Hogg-Dube syndrome (13)
10	-	-	not provided (10)
3	-	-	Birt-Hogg-Dube syndrome 1 (3)
2	-	-	Familial spontaneous pneumothorax (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:17p11.2 microduplication syndrome;CN074294:Nonpapillary renal cell carcinoma (1)
1	-	-	Colorectal cancer;C1868193:Familial spontaneous pneumothorax;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 (1)
1	-	-	FLCN-related disorder (1)
1	-	-	Inherited renal cancer (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80338682; hg19: chr17-17119708; COSMIC: COSV53257592; COSMIC: COSV53257592;