rs116643153

chr17-17221521-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000389169.9(FLCN):c.887T>A(p.Leu296Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,613,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L296L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: FLCN ENST00000389169.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3 O:1
• Conservation: PhyloP100: -0.626

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 5 uncertain in ENST00000389169.9
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056167245).
• BP6: Variant 17-17221521-A-T is Benign according to our data. Variant chr17-17221521-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 41860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17221521-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00139 (211/152278) while in subpopulation AFR AF= 0.00479 (199/41562). AF 95% confidence interval is 0.00424. There are 1 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7	c.871+16T>A		intron_variant		ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000389169.9	c.887T>A	p.Leu296Gln	missense_variant	8/8	1
FLCN	ENST00000285071.9	c.871+16T>A		intron_variant		1	NM_144997.7	P1
FLCN	ENST00000466317.1	n.730T>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 250878 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135690

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461410 Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90 AN XY: 727028

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.000514

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: 0.0000189

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74468

Gnomad4 AFR AF: 0.00479

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.00165

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jul 13, 2012

- -

FLCN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Birt-Hogg-Dube syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	0.85
Dann	Uncertain	0.98
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.40	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.10
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Polyphen		0.37	B
Vest4		0.18
MVP		0.19
ClinPred		0.0026	T
GERP RS		-2.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3

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: rs116643153; hg19: chr17-17124835;