rs3744124

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_144606.7(FLCN):c.907G>A(p.Gly303Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,613,860 control chromosomes in the GnomAD database, including 3,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 591 hom., cov: 32)

Exomes 𝑓: 0.058 ( 3372 hom. )

Consequence

FLCN
NM_144606.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -2.73

Publications

39 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
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: Orphanet, Ambry Genetics, Genomics England PanelApp
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001381129).

BP6

Variant 17-17221501-C-T is Benign according to our data. Variant chr17-17221501-C-T is described in ClinVar as Benign. ClinVar VariationId is 41861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144606.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLCN	NM_144997.7	MANE Select	c.871+36G>A		intron	N/A	NP_659434.2
FLCN	NM_144606.7		c.907G>A	p.Gly303Arg	missense	Exon 8 of 8	NP_653207.1	Q8NFG4-2
FLCN	NM_001353229.2		c.925+36G>A		intron	N/A	NP_001340158.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLCN	ENST00000389169.9	TSL:1	c.907G>A	p.Gly303Arg	missense	Exon 8 of 8	ENSP00000373821.5	Q8NFG4-2
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.871+36G>A		intron	N/A	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.149-2447G>A		intron	N/A	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes

AF:

0.0737

AC:

11211

AN:

152122

Hom.:

586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0411

Gnomad ASJ

AF:

0.0502

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.125

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0676

GnomAD2 exomes

AF:

0.0690

AC:

17323

AN:

250996

AF XY:

0.0712

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.0507

Gnomad EAS exome

AF:

0.194

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0463

Gnomad OTH exome

AF:

0.0518

GnomAD4 exome

AF:

0.0576

AC:

84152

AN:

1461620

Hom.:

3372

Cov.:

AF XY:

0.0595

AC XY:

43277

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.136

AC:

4551

AN:

33480

American (AMR)

AF:

0.0341

AC:

1523

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0525

AC:

1371

AN:

26136

East Asian (EAS)

AF:

0.183

AC:

7263

AN:

39700

South Asian (SAS)

AF:

0.125

AC:

10788

AN:

86258

European-Finnish (FIN)

AF:

0.0259

AC:

1375

AN:

53154

Middle Eastern (MID)

AF:

0.0827

AC:

477

AN:

5768

European-Non Finnish (NFE)

AF:

0.0474

AC:

52656

AN:

1112008

Other (OTH)

AF:

0.0687

AC:

4148

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

5960

11919

17879

23838

29798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2254

4508

6762

9016

11270

<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:

0.0738

AC:

11235

AN:

152240

Hom.:

591

Cov.:

AF XY:

0.0742

AC XY:

5523

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.128

AC:

5321

AN:

41534

American (AMR)

AF:

0.0410

AC:

627

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0502

AC:

174

AN:

3466

East Asian (EAS)

AF:

0.179

AC:

924

AN:

5156

South Asian (SAS)

AF:

0.126

AC:

608

AN:

4822

European-Finnish (FIN)

AF:

0.0239

AC:

254

AN:

10628

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3161

AN:

68026

Other (OTH)

AF:

0.0707

AC:

149

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

509

1018

1528

2037

2546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.0575

Hom.:

1607

Bravo

AF:

0.0791

TwinsUK

AF:

0.0502

AC:

186

ALSPAC

AF:

0.0472

AC:

182

ESP6500AA

AF:

0.131

AC:

579

ESP6500EA

AF:

0.0499

AC:

429

ExAC

AF:

0.0722

AC:

8763

Asia WGS

AF:

0.132

AC:

460

AN:

3478

EpiCase

AF:

0.0521

EpiControl

AF:

0.0472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Birt-Hogg-Dube syndrome (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.20

(source)

DANN

Benign

0.64

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

PhyloP100

-2.7

PROVEAN

Benign

-0.60

REVEL

Benign

0.23

Sift

Benign

0.38

Sift4G

Benign

0.56

Polyphen

0.0020

Vest4

0.083

MutPred

0.25

Gain of MoRF binding (P = 0.0251)

ClinPred

0.00059

GERP RS

-4.7

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.4

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over