dbSNP rs141250189: FLCN:p.Gln385His (chr17-17217090-C-A) – 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.1155G>T(p.Gln385His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000583 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. Q385L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.0110

Publications

0 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=0.02519995).

BP6

Variant 17-17217090-C-A is Benign according to our data. Variant chr17-17217090-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409383.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000335 (51/152272) while in subpopulation AFR AF = 0.00118 (49/41476). AF 95% confidence interval is 0.000918. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 51 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.1155G>T	p.Gln385His	missense	Exon 10 of 14	NP_659434.2
FLCN	NM_001353229.2		c.1209G>T	p.Gln403His	missense	Exon 12 of 16	NP_001340158.1
FLCN	NM_001353230.2		c.1155G>T	p.Gln385His	missense	Exon 11 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.1155G>T	p.Gln385His	missense	Exon 10 of 14	ENSP00000285071.4	Q8NFG4-1
ENSG00000264187	ENST00000427497.3	TSL:1	n.277G>T		non_coding_transcript_exon	Exon 6 of 12	ENSP00000394249.3	J3QW42
FLCN	ENST00000962729.1		c.1260G>T	p.Gln420His	missense	Exon 12 of 16	ENSP00000632788.1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000677

AC:

AN:

251056

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33462

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111290

Other (OTH)

AF:

0.0000663

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000335

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41476

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68048

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

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:

0.000586

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

Birt-Hogg-Dube syndrome (1)

Birt-Hogg-Dube syndrome 1 (1)

FLCN-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.2

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.72

M_CAP

Benign

0.016

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.95

PhyloP100

0.011

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.29

Sift

Benign

0.32

Sift4G

Benign

0.084

Polyphen

0.0

Vest4

0.21

MutPred

0.29

Loss of MoRF binding (P = 0.1846)

MVP

0.13

MPC

0.35

ClinPred

0.020

GERP RS

-5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.40

Mutation Taster

=54/46

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