rs34373805

Positions:

chr7-128846309-C-T

Variant summary

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

The NM_001458.5(FLNC):c.3973C>T(p.Leu1325=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,613,268 control chromosomes in the GnomAD database, including 36,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 8234 hom., cov: 33)

Exomes 𝑓: 0.18 ( 28004 hom. )

Consequence

FLNC
NM_001458.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.393

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=-0.7).

BP6

Variant 7-128846309-C-T is Benign according to our data. Variant chr7-128846309-C-T is described in ClinVar as [Benign]. Clinvar id is 129088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128846309-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.393 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.3973C>T	p.Leu1325=	synonymous_variant	23/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.3973C>T	p.Leu1325=	synonymous_variant	23/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.3973C>T	p.Leu1325=	synonymous_variant	23/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.3973C>T	p.Leu1325=	synonymous_variant	23/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42645

AN:

151926

Hom.:

8201

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.164

Gnomad OTH

AF:

0.249

GnomAD3 exomes

AF:

0.219

AC:

54420

AN:

248170

Hom.:

7450

AF XY:

0.211

AC XY:

28453

AN XY:

134772

show subpopulations

Gnomad AFR exome

AF:

0.551

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.423

Gnomad SAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.170

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.181

AC:

264678

AN:

1461224

Hom.:

28004

Cov.:

AF XY:

0.181

AC XY:

131491

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.553

Gnomad4 AMR exome

AF:

0.210

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.420

Gnomad4 SAS exome

AF:

0.201

Gnomad4 FIN exome

AF:

0.169

Gnomad4 NFE exome

AF:

0.160

Gnomad4 OTH exome

AF:

0.195

GnomAD4 genome

AF:

0.281

AC:

42729

AN:

152044

Hom.:

8234

Cov.:

AF XY:

0.279

AC XY:

20722

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.544

Gnomad4 AMR

AF:

0.191

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.425

Gnomad4 SAS

AF:

0.217

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.164

Gnomad4 OTH

AF:

0.251

Alfa

AF:

0.207

Hom.:

3025

Bravo

AF:

0.298

Asia WGS

AF:

0.315

AC:

1094

AN:

3478

EpiCase

AF:

0.163

EpiControl

AF:

0.163

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu1325Leu in exon 23 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 47.5% (2011/4238) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs34373805). -
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	Eurofins Ntd Llc (ga)	Jun 04, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 24, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.5

DANN

Benign

0.84

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