17-17215128-T-C

Variant names:

Variant summary

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

The NM_144997.7(FLCN):c.1433-38A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,376 control chromosomes in the GnomAD database, including 58,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.22 ( 4034 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54466 hom. )

Consequence

FLCN
NM_144997.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.802

Publications

11 publications found

Variant links:

COSMIC-nc: COSV53257291

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: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-17215128-T-C is Benign according to our data. Variant chr17-17215128-T-C is described in ClinVar as Benign. ClinVar VariationId is 253253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7 link	c.1433-38A>G		intron_variant	Intron 12 of 13	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
FLCN	ENST00000285071.9 link	c.1433-38A>G	intron_variant	Intron 12 of 13	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3 link	n.*267-38A>G	intron_variant	Intron 8 of 11	1		ENSP00000394249.3
MPRIP	ENST00000578209.5 link	c.*18-2362T>C	intron_variant	Intron 5 of 5	3		ENSP00000464276.1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32662

AN:

151540

Hom.:

4028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.230

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.00296

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.284

Gnomad MID

AF:

0.235

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.238

GnomAD2 exomes

AF:

0.233

AC:

58535

AN:

251172

AF XY:

0.237

show subpopulations

Gnomad AFR exome

AF:

0.113

Gnomad AMR exome

AF:

0.235

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.279

Gnomad NFE exome

AF:

0.278

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.266

AC:

388239

AN:

1461722

Hom.:

54466

Cov.:

AF XY:

0.265

AC XY:

192483

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.106

AC:

3535

AN:

33480

American (AMR)

AF:

0.232

AC:

10395

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

6026

AN:

26136

East Asian (EAS)

AF:

0.000529

AC:

AN:

39700

South Asian (SAS)

AF:

0.237

AC:

20458

AN:

86256

European-Finnish (FIN)

AF:

0.281

AC:

14952

AN:

53300

Middle Eastern (MID)

AF:

0.231

AC:

1331

AN:

5768

European-Non Finnish (NFE)

AF:

0.285

AC:

316585

AN:

1111970

Other (OTH)

AF:

0.247

AC:

14936

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

18336

36672

55008

73344

91680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10392

20784

31176

41568

51960

<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:

0.216

AC:

32692

AN:

151654

Hom.:

4034

Cov.:

AF XY:

0.217

AC XY:

16048

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.112

AC:

4641

AN:

41366

American (AMR)

AF:

0.230

AC:

3507

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

820

AN:

3472

East Asian (EAS)

AF:

0.00297

AC:

AN:

5058

South Asian (SAS)

AF:

0.220

AC:

1059

AN:

4814

European-Finnish (FIN)

AF:

0.284

AC:

3004

AN:

10560

Middle Eastern (MID)

AF:

0.231

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.276

AC:

18701

AN:

67834

Other (OTH)

AF:

0.235

AC:

495

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1298

2597

3895

5194

6492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.205

Hom.:

1036

Bravo

AF:

0.205

Asia WGS

AF:

0.0980

AC:

340

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Birt-Hogg-Dube syndrome

Benign:2

Jul 18, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jul 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.98

(source)

DANN

Benign

0.40

PhyloP100

-0.80

BranchPoint Hunter

4.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over