rs878855219

Positions:

• chr17-17223926-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_144997.7(FLCN):​c.614T>C​(p.Leu205Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 8.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.614T>C	p.Leu205Pro	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.614T>C	p.Leu205Pro	missense_variant	6/14	1	NM_144997.7	ENSP00000285071	P1
FLCN	ENST00000389169.9	c.614T>C	p.Leu205Pro	missense_variant	6/8	1		ENSP00000373821
FLCN	ENST00000417064.1	c.455T>C	p.Leu152Pro	missense_variant	4/4	2		ENSP00000410410
FLCN	ENST00000480316.1	n.580T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460946 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 726778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:Potocki-Lupski syndrome;CN074294:Nonpapillary renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Birt-Hogg-Dube syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 205 of the FLCN protein (p.Leu205Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 241929). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLCN protein function. 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.40	N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.56	P;D;.
Vest4		0.86
MutPred		0.57		Gain of relative solvent accessibility (P = 0.0104);Gain of relative solvent accessibility (P = 0.0104);.;
MVP		0.40
MPC		0.85
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.75
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs878855219; hg19: chr17-17127240;