chr7-128848607-C-T

Position:

chr7-128848607-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2

The ENST00000325888.13(FLNC):c.4627C>T(p.Arg1543Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1543Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

FLNC
ENST00000325888.13 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.486

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in ENST00000325888.13

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNC. . Gene score misZ 2.789 (greater than the threshold 3.09). Trascript score misZ 5.9457 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, heart conduction disease, familial isolated restrictive cardiomyopathy, hypertrophic cardiomyopathy 26, distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.4627C>T	p.Arg1543Trp	missense_variant	27/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.4627C>T	p.Arg1543Trp	missense_variant	27/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.4627C>T	p.Arg1543Trp	missense_variant	27/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.4627C>T	p.Arg1543Trp	missense_variant	27/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

249058

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461440

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000568

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2022	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2022

The p.R1543W variant (also known as c.4627C>T), located in coding exon 27 of the FLNC gene, results from a C to T substitution at nucleotide position 4627. The arginine at codon 1543 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1543 of the FLNC protein (p.Arg1543Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 472073). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.59

Loss of disorder (P = 0.0121);Loss of disorder (P = 0.0121);

MVP

0.71

MPC

0.99

ClinPred

0.99

GERP RS

4.2

Varity_R

0.63

gMVP

0.64

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