7-128851549-T-C

Position:

• chr7-128851549-T-C

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.5763T>C​(p.Thr1921=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0813 in 1,613,870 control chromosomes in the GnomAD database, including 14,730 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. T1921T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (5273 hom., cov: 33)
  • Exomes 𝑓: 0.071 (9457 hom.)
• Consequence: FLNC NM_001458.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -6.58

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-AS1 (HGNC:53474): (FLNC antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-128851549-T-C is Benign according to our data. Variant chr7-128851549-T-C is described in ClinVar as [Benign]. Clinvar id is 129094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128851549-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNC	NM_001458.5	c.5763T>C	p.Thr1921=	synonymous_variant	35/48	ENST00000325888.13
FLNC-AS1	NR_149055.1	n.216-49A>G		intron_variant, non_coding_transcript_variant
FLNC	NM_001127487.2	c.5664T>C	p.Thr1888=	synonymous_variant	34/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNC	ENST00000325888.13	c.5763T>C	p.Thr1921=	synonymous_variant	35/48	1	NM_001458.5	P3
FLNC	ENST00000346177.6	c.5664T>C	p.Thr1888=	synonymous_variant	34/47	1		A1
FLNC-AS1	ENST00000469965.1	n.216-49A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27646 AN: 152124 Hom.: 5263 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.125 AC: 31322 AN: 250952 Hom.: 4181 AF XY: 0.116 AC XY: 15801 AN XY: 135754

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0910

GnomAD4 exome AF: 0.0709 AC: 103562 AN: 1461628 Hom.: 9457 Cov.: 34 AF XY: 0.0720 AC XY: 52344 AN XY: 727134

Gnomad4 AFR exome AF: 0.478

Gnomad4 AMR exome AF: 0.161

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.334

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0403

Gnomad4 OTH exome AF: 0.0924

GnomAD4 genome AF: 0.182 AC: 27684 AN: 152242 Hom.: 5273 Cov.: 33 AF XY: 0.181 AC XY: 13449 AN XY: 74458

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.0428

Gnomad4 OTH AF: 0.139

Alfa AF: 0.0638 Hom.: 1491

Bravo AF: 0.203

Asia WGS AF: 0.272 AC: 943 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0443

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr1921Thr in exon 35 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 46.2% (2036/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3816884). -
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)	Jan 29, 2016	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.038
DANN	Benign	0.37

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: rs3816884; hg19: chr7-128491603; COSMIC: COSV57957802;