chr17-17226239-G-C

Position:

• chr17-17226239-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BS2_Supporting

The NM_144997.7(FLCN):​c.333C>G​(p.His111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: FLCN NM_144997.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.45

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.37276033).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.333C>G	p.His111Gln	missense_variant	5/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.333C>G	p.His111Gln	missense_variant	5/14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.148+1751C>G		intron_variant		1		ENSP00000394249.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 11, 2022

The p.H111Q variant (also known as c.333C>G), located in coding exon 2 of the FLCN gene, results from a C to G substitution at nucleotide position 333. The histidine at codon 111 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Birt-Hogg-Dube syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 111 of the FLCN protein (p.His111Gln). 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: 1017026). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.045	D;T;T
Sift4G	Uncertain	0.028	D;T;T
Polyphen		0.51	P;D;.
Vest4		0.78
MutPred		0.28		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);.;
MVP		0.54
MPC		0.58
ClinPred		0.73	D
GERP RS		2.6
Varity_R		0.55
gMVP		0.53

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: rs1555610924; hg19: chr17-17129553;