rs786203348

Positions:

chr17-17216406-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_144997.7(FLCN):c.1274A>G(p.Gln425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. Q425H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

FLCN
NM_144997.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.06

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:

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 made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_144997.7

BP4

Computational evidence support a benign effect (MetaRNN=0.2814504).

BP6

Variant 17-17216406-T-C is Benign according to our data. Variant chr17-17216406-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186952.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}. Variant chr17-17216406-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.1274A>G	p.Gln425Arg	missense_variant	11/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.1274A>G	p.Gln425Arg	missense_variant	11/14	1	NM_144997.7	P1	Q8NFG4-1
MPRIP	ENST00000578209.5 linkuse as main transcript	c.*18-1084T>C		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

248696

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461376

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000747

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Birt-Hogg-Dube syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 07, 2019	This FLCN variant (rs786203348) is rare (<0.1%) in a large population dataset (gnomAD: 9/280056 total alleles; 0.0032%; no homozygotes). This variant has not been reported in the literature, to our knowledge. Two submitters in ClinVar classify c.1274A>G as a variant of uncertain clinical significance. Three bioinformatic tools queried predict that this substitution would be tolerated, and the glutamine residue at this position is poorly evolutionarily conserved across species assessed. Due to lack of funtional and segregation studies, we consider the clinical significance of c.1274A>G to be uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

FLCN-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

The FLCN c.1274A>G variant is predicted to result in the amino acid substitution p.Gln425Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0055% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17119720-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17028174) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.020

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.28

MetaSVM

Uncertain

-0.060

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.85

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.99

REVEL

Benign

0.28

Sift

Benign

0.24

Sift4G

Benign

0.38

Polyphen

0.0070

Vest4

0.53

MVP

0.34

MPC

0.40

ClinPred

0.051

GERP RS

4.8

Varity_R

0.19

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over