rs61750032

Positions:

• chr17-17216447-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000285071.9(FLCN):​c.1233G>A​(p.Glu411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00791 in 1,613,828 control chromosomes in the GnomAD database, including 514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (247 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (267 hom.)
• Consequence: FLCN ENST00000285071.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.21

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]

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 17-17216447-C-T is Benign according to our data. Variant chr17-17216447-C-T is described in ClinVar as [Benign]. Clinvar id is 96474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-17216447-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLCN	NM_144997.7	c.1233G>A	p.Glu411=	synonymous_variant	11/14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.1233G>A	p.Glu411=	synonymous_variant	11/14	1	NM_144997.7	ENSP00000285071	P1
MPRIP	ENST00000578209.5	c.*18-1043C>T		intron_variant		3		ENSP00000464276

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5023 AN: 152162 Hom.: 245 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0105 AC: 2616 AN: 249546 Hom.: 112 AF XY: 0.00805 AC XY: 1088 AN XY: 135176

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00529 AC: 7730 AN: 1461548 Hom.: 267 Cov.: 31 AF XY: 0.00478 AC XY: 3479 AN XY: 727082

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0330 AC: 5032 AN: 152280 Hom.: 247 Cov.: 32 AF XY: 0.0317 AC XY: 2363 AN XY: 74468

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0185

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0159 Hom.: 58

Bravo AF: 0.0382

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00439

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu411Glu in exon 11 of FLCN: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 10.6% (468/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs61750032). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The c.1233G>A (p.Glu441Glu) variant in FLCN affects a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice-tools in Alamut predict no significant effect on splicing, although these predictions have yet to be confirmed by functional studies. This variant is found in 1437/117988 control chromosomes (58 homozygotes) at a frequency of 0.0121792, which is about 9743 times of the maximal expected frequency of a pathogenic allele (0.0000013), strong evidence that this variant is benign. In addition, multiple reputable clinical laboratories have classified this variant as benign. Taken together, this variant was classified as benign. -

Birt-Hogg-Dube syndrome Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2014

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.9
DANN	Benign	0.90

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

Other links and lift over

dbSNP: rs61750032; hg19: chr17-17119761;