17-17227974-T-C

Position:

• chr17-17227974-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144997.7(FLCN):​c.164A>G​(p.Asn55Ser) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.98

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06890902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.164A>G	p.Asn55Ser	missense_variant	4/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.164A>G	p.Asn55Ser	missense_variant	4/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+16A>G		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2015

The p.N55S variant (also known as c.164A>G), located in coding exon 1 of the FLCN gene, results from an A to G substitution at nucleotide position 164. The asparagine at codon 55 is replaced by serine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 4500 alleles tested) in our clinical cohort. This amino acid position is highly conserved through reptiles. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.N55S remains unclear. -

Birt-Hogg-Dube syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 232994). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 55 of the FLCN protein (p.Asn55Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.4	N;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.87	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.19
MutPred		0.22		Gain of phosphorylation at N55 (P = 0.017);Gain of phosphorylation at N55 (P = 0.017);.;
MVP		0.068
MPC		0.29
ClinPred		0.22	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs876660119; hg19: chr17-17131288;