17-17216395-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_144997.7(FLCN):c.1285C>G(p.His429Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. H429N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.28

Publications

6 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 links:

ENSG00000264187 (HGNC:):

ENSG00000264187 links:

MPRIP (HGNC:30321): (myosin phosphatase Rho interacting protein) Enables cadherin binding activity. Predicted to be involved in actin filament organization. Located in actin cytoskeleton and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

MPRIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 34 uncertain in NM_144997.7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

BS2

High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144997.7. 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.1285C>G	p.His429Asp	missense	Exon 11 of 14	NP_659434.2
FLCN	NM_001353229.2		c.1339C>G	p.His447Asp	missense	Exon 13 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.1285C>G	p.His429Asp	missense	Exon 12 of 15	NP_001340159.1	Q8NFG4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FLCN	ENST00000285071.9	TSL:1 MANE Select	c.1285C>G	p.His429Asp	missense	Exon 11 of 14	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.*119C>G		non_coding_transcript_exon	Exon 7 of 12	ENSP00000394249.3	J3QW42
ENSG00000264187	ENST00000427497.3	TSL:1	n.*119C>G		3_prime_UTR	Exon 7 of 12	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000817

AC:

AN:

244706

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459798

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726190

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26072

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110936

Other (OTH)

AF:

0.0000332

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Birt-Hogg-Dube syndrome (1)

Birt-Hogg-Dube syndrome 1 (1)

Birt-Hogg-Dube syndrome;C0346629:Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:17p11.2 microduplication syndrome;CN074294:Nonpapillary renal cell carcinoma (1)

Hereditary cancer-predisposing syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.2

PhyloP100

7.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.67

Sift

Benign

0.19

Sift4G

Uncertain

0.0090

Polyphen

0.33

Vest4

0.82

MVP

0.44

MPC

0.57

ClinPred

0.93

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.76

gMVP

0.78

Mutation Taster

=53/47

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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