rs752006809

Variant names:

• chr17-17216491-C-A
• rs752006809
• NM_144997.7:c.1189G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-17216491-C-A
• chr17-17216491-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001353229.2(FLCN):​c.1243G>T​(p.Val415Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V415M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN NM_001353229.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.46
• Publications: 7 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.393032).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353229.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	NM_144997.7	MANE Select	c.1189G>T	p.Val397Leu	missense	Exon 11 of 14	NP_659434.2
	FLCN	NM_001353229.2		c.1243G>T	p.Val415Leu	missense	Exon 13 of 16	NP_001340158.1
	FLCN	NM_001353230.2		c.1189G>T	p.Val397Leu	missense	Exon 12 of 15	NP_001340159.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1189G>T	p.Val397Leu	missense	Exon 11 of 14	ENSP00000285071.4
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*23G>T		non_coding_transcript_exon	Exon 7 of 12	ENSP00000394249.3
	ENSG00000264187	ENST00000427497.3	TSL:1	n.*23G>T		3_prime_UTR	Exon 7 of 12	ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.010	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.40
Sift	Benign	0.071	T
Sift4G	Benign	0.10	T
Polyphen		0.0080	B
Vest4		0.68
MutPred		0.39		Loss of sheet (P = 0.0181)
MVP		0.18
MPC		0.59
ClinPred		0.70	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs752006809; hg19: chr17-17119805;