chr17-17215282-T-TGCGGCTGCGTGGACCTC

Variant names:

• chr17-17215282-T-TGCGGCTGCGTGGACCTC
• rs879255677
• NM_144997.7:c.1318_1334dupGAGGTCCACGCAGCCGC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_144997.7(FLCN):​c.1318_1334dupGAGGTCCACGCAGCCGC​(p.Leu449GlnfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A445A) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.05
• Publications: 2 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-17215282-T-TGCGGCTGCGTGGACCTC is Pathogenic according to our data. Variant chr17-17215282-T-TGCGGCTGCGTGGACCTC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 253249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

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.1318_1334dupGAGGTCCACGCAGCCGC	p.Leu449GlnfsTer25	frameshift	Exon 12 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1372_1388dupGAGGTCCACGCAGCCGC	p.Leu467GlnfsTer25	frameshift	Exon 14 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.1318_1334dupGAGGTCCACGCAGCCGC	p.Leu449GlnfsTer25	frameshift	Exon 13 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.1318_1334dupGAGGTCCACGCAGCCGC	p.Leu449GlnfsTer25	frameshift	Exon 12 of 14	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*152_*168dupGAGGTCCACGCAGCCGC		non_coding_transcript_exon	Exon 8 of 12	ENSP00000394249.3	J3QW42
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*152_*168dupGAGGTCCACGCAGCCGC		3_prime_UTR	Exon 8 of 12	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461834 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
3	-	-	Birt-Hogg-Dube syndrome (3)
2	-	-	Birt-Hogg-Dube syndrome 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs879255677; hg19: chr17-17118596;