rs3734973

Variant names:

• chr7-128844762-A-G
• rs3734973
• NM_001458.5:c.3297A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (8463 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30386 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.527

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]

ACMG classification

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 rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.3297A>G	p.Val1099Val	synonymous_variant	Exon 21 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43109 AN: 152070 Hom.: 8435 Cov.: 33

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

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.: 36 AF XY: 0.188 AC XY: 136465 AN XY: 727126

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.: 33 AF XY: 0.280 AC XY: 20842 AN XY: 74416

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

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

- -

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

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2015

PreventionGenetics, part of Exact Sciences

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
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

Other links and lift over

dbSNP: rs3734973; hg19: chr7-128484816; COSMIC: COSV57950410; COSMIC: COSV57950410;