Genetic Variant NM_144997.7:c.1333G>A (chr17-17215284-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144997.7(FLCN):c.1333G>A(p.Ala445Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,082 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A445G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:24O:1

Conservation

PhyloP100: -0.0320

Publications

25 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004835129).

BP6

Variant 17-17215284-C-T is Benign according to our data. Variant chr17-17215284-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3370.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00244 (372/152276) while in subpopulation AMR AF = 0.00588 (90/15298). AF 95% confidence interval is 0.0049. There are 0 homozygotes in GnomAd4. There are 174 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 372 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.1333G>A	p.Ala445Thr	missense	Exon 12 of 14	NP_659434.2
FLCN	NM_001353229.2		c.1387G>A	p.Ala463Thr	missense	Exon 14 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.1333G>A	p.Ala445Thr	missense	Exon 13 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.1333G>A	p.Ala445Thr	missense	Exon 12 of 14	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.*167G>A		non_coding_transcript_exon	Exon 8 of 12	ENSP00000394249.3	J3QW42
ENSG00000264187	ENST00000427497.3	TSL:1	n.*167G>A		3_prime_UTR	Exon 8 of 12	ENSP00000394249.3	J3QW42

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

372

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00334

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00264

AC:

662

AN:

251048

AF XY:

0.00280

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000648

Gnomad NFE exome

AF:

0.00370

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00298

AC:

4358

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

2235

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.00212

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00398

AC:

343

AN:

86258

European-Finnish (FIN)

AF:

0.000712

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00318

AC:

3534

AN:

1112004

Other (OTH)

AF:

0.00318

AC:

192

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

300

600

900

1200

1500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00244

AC:

372

AN:

152276

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41566

American (AMR)

AF:

0.00588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00334

AC:

227

AN:

68022

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00280

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00270

AC:

328

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00397

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (10)

Birt-Hogg-Dube syndrome (7)

not specified (6)

Hereditary cancer-predisposing syndrome (2)

Carcinoma of colon (1)

Colorectal cancer;C1868193:Familial spontaneous pneumothorax;C2931246:17p11.2 microduplication syndrome;CN074294:Nonpapillary renal cell carcinoma;CN375946:Birt-Hogg-Dube syndrome 1 (1)

Familial spontaneous pneumothorax (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.11

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.31

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.60

M_CAP

Benign

0.060

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-1.0

PhyloP100

-0.032

PrimateAI

Benign

0.29

PROVEAN

Benign

0.19

REVEL

Benign

0.20

Sift

Benign

0.87

Sift4G

Benign

0.55

Polyphen

0.0

Vest4

0.20

MVP

0.19

MPC

0.36

ClinPred

0.0014

GERP RS

-7.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.024

gMVP

0.20

Mutation Taster

=95/5

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

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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