rs532143625

Positions:

chr7-128837983-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_001458.5(FLNC):c.970-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

FLNC
NM_001458.5 splice_region, intron

Scores

Splicing: ADA: 0.8501

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: -0.341

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 7-128837983-A-G is Pathogenic according to our data. Variant chr7-128837983-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432231.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2}. Variant chr7-128837983-A-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.970-4A>G		splice_region_variant, intron_variant		ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 linkuse as main transcript	c.970-4A>G		splice_region_variant, intron_variant			NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.970-4A>G		splice_region_variant, intron_variant		1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.970-4A>G		splice_region_variant, intron_variant		1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249292

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1461278

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000268

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000138

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000173

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Arrhythmogenic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Roden Lab, Vanderbilt University Medical Center

Oct 28, 2022

Truncating variants in FLNC are reported to cause a highly penetrant form of arrhythmogenic cardiomyopathy (Gigli, Circulation, 2021). The FLNC c.970-4A>G variant was identified in 4 probands with arrhythmogenic cardiomyopathy, and the variant cosegregated with phenotype in heterozygous family members. Computational tools predicted that the variant activated a cryptic splice acceptor site 3 nucleotides adjacent to the canonical site, leading to inclusion of an in-frame premature termination codon in the mature mRNA. Functional studies confirmed this molecular event in peripheral blood and iPSC-CM RNA analyses, provoking a phenotype consistent with other truncating FLNC variants. These data collectively support criteria to classify FLNC c.970-4A>G as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change falls in intron 5 of the FLNC gene. It does not directly change the encoded amino acid sequence of the FLNC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs532143625, gnomAD 0.009%). This variant has been observed in individuals with clinical features of FLNC-related conditions (PMID: 32112656, 34587765, 37164047; Invitae). ClinVar contains an entry for this variant (Variation ID: 432231). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 37164047). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 18, 2022

- -

Myofibrillar myopathy 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 11, 2021

This sequence change falls in the splice region of the acceptor site of intron 5 of FLNC. The variant is present in a large population cohort at a frequency of 0.005% (rs532143625, 15/280,590 alleles, 0 homozygotes in gnomAD v2.1). It has been classified as a variant of uncertain significance and pathogenic previously (ClinVar, LOVD). The variant has been identified in at least two probands with dilated cardiomyopathy (PMID: 32112656, Shariant), and compound heterozygous with a second pathogenic allele in an individual with cardiomyopathy (https://doi.org/10.1161/res.127.suppl_1.454). The nucleotide is not conserved (100 vertebrates, UCSC), and multiple lines of computational evidence predict a impact on splicing (SpliceAI, MaxEntScan, NNSplice). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PP3. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2024

Identified in patients with cardiomyopathy, including DCM and ACM in published literature; several patients harbored additional cardiogenetic variants (PMID: 32112656, 34587765, 37164047); Identified in an abstract by Ohiri, 2020 in trans with a nonsense variant in the FLNC gene in a patient with postpartum cardiomyopathy and skeletal muscle disease; A published functional study demonstrates a damaging effect as c.970-4A>G activated the cryptic SAS, introducing a 3-bp insertion which results in protein truncation and nonsense mediated decay; patch clamp studies also showed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current (PMID: 37164047); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32112656, 37164047, 34587765) -

FLNC-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The FLNC c.970-4A>G variant is predicted to interfere with splicing. This variant has been reported in an individual with dilated cardiomyopathy (Verdonschot et al. 2020. PubMed ID: 32112656, table 1) and in an additional large cohort study of patients with FLNC truncating variants and varied cardiac phenotypes (Gigli et al. 2021. PubMed ID: 34587765). An outside laboratory indicated this variant was detected in 4 probands with segregation in affected family members; however, additional details were not provided (https://www.ncbi.nlm.nih.gov/clinvar/variation/432231/). This variant is reported in 0.010% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2024

The c.970-4A>G intronic variant results from an A to G substitution 4 nucleotides before coding exon 6 in the FLNC gene. This variant has been detected in probands with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy, and has shown some segregation with disease features in families; however, in some cases, clinical details were limited or additional variants in cardiac-related genes were detected (Verdonschot JAJ et al. Hum Mutat, 2020 06;41:1091-1111; Gigli M et al. Circulation. 2021 Nov;144(20):1600-1611; O'Neill MJ et al. Heart Rhythm. 2023 Aug;20(8):1158-1166). RNA studies by one group have indicated that this alteration results in abnormal splicing (O'Neill MJ et al. Heart Rhythm. 2023 Aug;20(8):1158-1166). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.88

Position offset: 1

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