Genetic Variant FLCN:c.871+684G>A (chr17-17220853-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_144997.7(FLCN):c.871+684G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 224,338 control chromosomes in the GnomAD database, including 3,124 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2346 hom., cov: 32)

Exomes 𝑓: 0.13 ( 778 hom. )

Consequence

FLCN
NM_144997.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.366

Publications

5 publications found

Variant links:

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]

FLCN Gene-Disease associations (from GenCC):

Birt-Hogg-Dube syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Birt-Hogg-Dube syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
familial spontaneous pneumothorax
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
renal carcinoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

FLCN links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7 link	c.871+684G>A		intron_variant	Intron 8 of 13	ENST00000285071.9	NP_659434.2	Q8NFG4-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FLCN	ENST00000285071.9 link	c.871+684G>A	intron_variant	Intron 8 of 13	1	NM_144997.7	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3 link	n.149-1799G>A	intron_variant	Intron 4 of 11	1		ENSP00000394249.3	J3QW42
FLCN	ENST00000466317.1 link	n.1398G>A	non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

25992

AN:

152016

Hom.:

2342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.00462

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.165

Gnomad OTH

AF:

0.189

GnomAD4 exome

AF:

0.128

AC:

9258

AN:

72204

Hom.:

778

Cov.:

AF XY:

0.127

AC XY:

4783

AN XY:

37582

show subpopulations

African (AFR)

AF:

0.186

AC:

264

AN:

1418

American (AMR)

AF:

0.153

AC:

561

AN:

3674

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

302

AN:

1722

East Asian (EAS)

AF:

0.00565

AC:

AN:

4250

South Asian (SAS)

AF:

0.116

AC:

1220

AN:

10482

European-Finnish (FIN)

AF:

0.0889

AC:

293

AN:

3294

Middle Eastern (MID)

AF:

0.223

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.138

AC:

5974

AN:

43240

Other (OTH)

AF:

0.145

AC:

561

AN:

3860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

365

729

1094

1458

1823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.171

AC:

26018

AN:

152134

Hom.:

2346

Cov.:

AF XY:

0.169

AC XY:

12582

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.222

AC:

9195

AN:

41494

American (AMR)

AF:

0.160

AC:

2442

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

652

AN:

3466

East Asian (EAS)

AF:

0.00463

AC:

AN:

5186

South Asian (SAS)

AF:

0.129

AC:

620

AN:

4812

European-Finnish (FIN)

AF:

0.119

AC:

1263

AN:

10576

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.165

AC:

11205

AN:

68000

Other (OTH)

AF:

0.188

AC:

396

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1109

2218

3328

4437

5546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

280

560

840

1120

1400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.173

Hom.:

491

Bravo

AF:

0.176

Asia WGS

AF:

0.0750

AC:

261

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.3

(source)

DANN

Benign

0.50

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over