17-17213213-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_144997.7(FLCN):c.*442T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 378,794 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 64 hom., cov: 32)

Exomes 𝑓: 0.020 ( 59 hom. )

Consequence

FLCN
NM_144997.7 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.755

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 17-17213213-A-G is Benign according to our data. Variant chr17-17213213-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 322051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0242 (3686/152314) while in subpopulation AFR AF= 0.0402 (1672/41574). AF 95% confidence interval is 0.0386. There are 64 homozygotes in gnomad4. There are 1720 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 3685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLCN	NM_144997.7 linkuse as main transcript	c.*442T>C		3_prime_UTR_variant	14/14	ENST00000285071.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLCN	ENST00000285071.9 linkuse as main transcript	c.*442T>C		3_prime_UTR_variant	14/14	1	NM_144997.7	P1	Q8NFG4-1
MPRIP	ENST00000578209.5 linkuse as main transcript	c.*18-4277A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3685

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0403

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0221

Gnomad OTH

AF:

0.0224

GnomAD4 exome

AF:

0.0196

AC:

4446

AN:

226480

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

2177

AN XY:

114702

show subpopulations

Gnomad4 AFR exome

AF:

0.0426

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.00498

Gnomad4 EAS exome

AF:

0.00773

Gnomad4 SAS exome

AF:

0.0193

Gnomad4 FIN exome

AF:

0.00612

Gnomad4 NFE exome

AF:

0.0217

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0242

AC:

3686

AN:

152314

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1720

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0402

Gnomad4 AMR

AF:

0.0186

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.0188

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.0222

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0223

Hom.:

Bravo

AF:

0.0255

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial spontaneous pneumothorax

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Birt-Hogg-Dube syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

Cadd

Benign

1.8

Dann

Benign

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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