17-17226304-C-T

Position:

• chr17-17226304-C-T

Variant summary

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

The ENST00000285071.9(FLCN):​c.268G>A​(p.Ala90Thr) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A90S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLCN ENST00000285071.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.71

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19499505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.268G>A	p.Ala90Thr	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.268G>A	p.Ala90Thr	missense_variant	5/14	1	NM_144997.7	ENSP00000285071	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Mar 01, 2022

The p.A90T variant (also known as c.268G>A), located in coding exon 2 of the FLCN gene, results from a G to A substitution at nucleotide position 268. The alanine at codon 90 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Oct 22, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 90 of the FLCN protein (p.Ala90Thr). 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: 821675). 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	Benign	0.073
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	-0.0094
Eigen_PC	Benign	0.084
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.76	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0070	B;P;.
Vest4		0.19
MutPred		0.15		Gain of glycosylation at A90 (P = 0.0106);Gain of glycosylation at A90 (P = 0.0106);.;
MVP		0.41
MPC		0.36
ClinPred		0.61	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.19

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: rs141140415; hg19: chr17-17129618;