rs3734973

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):c.3297A>G(p.Val1099Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,820 control chromosomes in the GnomAD database, including 38,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1099V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 8463 hom., cov: 33)

Exomes 𝑓: 0.19 ( 30386 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.527

Publications

22 publications found

Variant links:

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

FLNC Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
myofibrillar myopathy 5
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
hypertrophic cardiomyopathy 26
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
distal myopathy with posterior leg and anterior hand involvement
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

FLNC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 7-128844762-A-G is Benign according to our data. Variant chr7-128844762-A-G is described in ClinVar as Benign. ClinVar VariationId is 129084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.527 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 48	1	NM_001458.5	ENSP00000327145.8		Q14315-1

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

43109

AN:

152070

Hom.:

8435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.548

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.136

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.254

GnomAD2 exomes

AF:

0.225

AC:

56011

AN:

249332

AF XY:

0.218

show subpopulations

Gnomad AFR exome

AF:

0.553

Gnomad AMR exome

AF:

0.207

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.460

Gnomad FIN exome

AF:

0.139

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.187

AC:

273588

AN:

1461632

Hom.:

30386

Cov.:

AF XY:

0.188

AC XY:

136465

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.556

AC:

18602

AN:

33480

American (AMR)

AF:

0.209

AC:

9347

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3322

AN:

26136

East Asian (EAS)

AF:

0.464

AC:

18413

AN:

39700

South Asian (SAS)

AF:

0.257

AC:

22144

AN:

86258

European-Finnish (FIN)

AF:

0.141

AC:

7505

AN:

53202

Middle Eastern (MID)

AF:

0.137

AC:

793

AN:

5768

European-Non Finnish (NFE)

AF:

0.163

AC:

180985

AN:

1111976

Other (OTH)

AF:

0.207

AC:

12477

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

13978

27956

41935

55913

69891

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6804

13608

20412

27216

34020

<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:

0.284

AC:

43175

AN:

152188

Hom.:

8463

Cov.:

AF XY:

0.280

AC XY:

20842

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.548

AC:

22749

AN:

41504

American (AMR)

AF:

0.187

AC:

2855

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.136

AC:

472

AN:

3468

East Asian (EAS)

AF:

0.468

AC:

2419

AN:

5166

South Asian (SAS)

AF:

0.281

AC:

1359

AN:

4830

European-Finnish (FIN)

AF:

0.130

AC:

1379

AN:

10620

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11288

AN:

67996

Other (OTH)

AF:

0.256

AC:

540

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1406

2813

4219

5626

7032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

408

816

1224

1632

2040

<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:

0.207

Hom.:

5090

Bravo

AF:

0.300

Asia WGS

AF:

0.385

AC:

1335

AN:

3478

EpiCase

AF:

0.167

EpiControl

AF:

0.162

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Dec 30, 2015

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Val1099Val in exon 21 of FLNC: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 48.3% (1996/4136) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3734973). -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 12, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.3

(source)

DANN

Benign

0.67

PhyloP100

0.53

Mutation Taster

=91/9

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over