rs876657646

Positions:

• chr17-17223987-A-G
• chr17-17223987-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_144997.7(FLCN):​c.553T>C​(p.Ser185Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.68

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain uDENN FLCN/SMCR8-type (size 156) in uniprot entity FLCN_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_144997.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 17-17223987-A-G is Pathogenic according to our data. Variant chr17-17223987-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228263.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.553T>C	p.Ser185Pro	missense_variant	6/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.553T>C	p.Ser185Pro	missense_variant	6/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+4003T>C		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Birt-Hogg-Dube syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 30, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 228263). This missense change has been observed in individuals with Birt-Hogg-Dube´ syndrome (PMID: 23414156; Invitae). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 185 of the FLCN protein (p.Ser185Pro). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2017	The p.Ser185Pro variant in FLCN has been reported in 1 individual with Birt Hogg Dube syndrome (BHDS), segregated with disease in 2 affected relatives (Mota-Bur gos 2013, LMM unpublished data), and was absent from large population studies. F LCN is the only gene known to be associated with BHDS and a disease causing vari ant is present in ~90% of patients. Other supporting evidence includes a strong evolutionary conservation of the affected amino acid, suggesting that a change w ould not be tolerated. In summary, although additional studies are required to f ully establish its clinical significance, the p.Ser185Pro variant is likely path ogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D;D;T
Sift4G	Uncertain	0.037	D;T;T
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.55		Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;
MVP		0.84
MPC		1.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657646; hg19: chr17-17127301;