rs3734973

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001458.5(FLNC):c.3297A>G(p.Val1099=) 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 (★★).

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:10

Conservation

PhyloP100: 0.527

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 129084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128844762-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.3297A>G	p.Val1099=	synonymous_variant	21/48	ENST00000325888.13
FLNC	NM_001127487.2 linkuse as main transcript	c.3297A>G	p.Val1099=	synonymous_variant	21/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.3297A>G	p.Val1099=	synonymous_variant	21/48	1	NM_001458.5	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.3297A>G	p.Val1099=	synonymous_variant	21/47	1		A1	Q14315-2

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

GnomAD3 exomes

AF:

0.225

AC:

56011

AN:

249332

Hom.:

8130

AF XY:

0.218

AC XY:

29547

AN XY:

135330

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 SAS exome

AF:

0.258

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

Gnomad4 AFR exome

AF:

0.556

Gnomad4 AMR exome

AF:

0.209

Gnomad4 ASJ exome

AF:

0.127

Gnomad4 EAS exome

AF:

0.464

Gnomad4 SAS exome

AF:

0.257

Gnomad4 FIN exome

AF:

0.141

Gnomad4 NFE exome

AF:

0.163

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.284

AC:

43175

AN:

152188

Hom.:

8463

Cov.:

AF XY:

0.280

AC XY:

20842

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.548

Gnomad4 AMR

AF:

0.187

Gnomad4 ASJ

AF:

0.136

Gnomad4 EAS

AF:

0.468

Gnomad4 SAS

AF:

0.281

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.166

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.203

Hom.:

2865

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 12, 2017

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

Cadd

Benign

7.3

Dann

Benign

0.67

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