NM_144997.7:c.1300+5G>C

Variant names:

• chr17-17216375-C-G
• rs746264578
• NM_144997.7:c.1300+5G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_144997.7(FLCN):​c.1300+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001199890: Studies have shown that this variant results in skipping of exon 11, and produces a non-functional protein and/or introduces a premature termination codon (internal data)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_144997.7 splice_region, intron
• Scores: Splicing: ADA: 0.9980
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.15
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001199890: Studies have shown that this variant results in skipping of exon 11, and produces a non-functional protein and/or introduces a premature termination codon (internal data).; SCV002691105: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 17-17216375-C-G is Pathogenic according to our data. Variant chr17-17216375-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 835599.

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.1300+5G>C		splice_region intron	N/A	NP_659434.2
	FLCN	NM_001353229.2		c.1354+5G>C		splice_region intron	N/A	NP_001340158.1
	FLCN	NM_001353230.2		c.1300+5G>C		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.1300+5G>C		splice_region intron	N/A	ENSP00000285071.4	Q8NFG4-1
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*134+5G>C		splice_region intron	N/A	ENSP00000394249.3	J3QW42
	FLCN	ENST00000962729.1		c.1405+5G>C		splice_region intron	N/A	ENSP00000632788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Birt-Hogg-Dube syndrome (1)
-	1	-	FLCN-related disorder (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.82
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: 5

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

Other links and lift over

dbSNP: rs746264578; hg19: chr17-17119689;