rs765435961

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001458.5(FLNC):c.4413A>T(p.Gln1471His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: -0.329

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22388536).

BS2

High AC in GnomAdExome4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5 link	c.4413A>T	p.Gln1471His	missense_variant	Exon 25 of 48	ENST00000325888.13	NP_001449.3	Q14315-1Q59H94
FLNC	NM_001127487.2 link	c.4413A>T	p.Gln1471His	missense_variant	Exon 25 of 47		NP_001120959.1	Q14315-2Q59H94

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 link	c.4413A>T	p.Gln1471His	missense_variant	Exon 25 of 48	1	NM_001458.5	ENSP00000327145.8		Q14315-1
FLNC	ENST00000346177.6 link	c.4413A>T	p.Gln1471His	missense_variant	Exon 25 of 47	1		ENSP00000344002.6		Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

248982

Hom.:

AF XY:

0.0000666

AC XY:

AN XY:

135164

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:

0.0000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461416

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000603

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000848

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Dec 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FLNC c.4413A>T (p.Gln1471His) results in a non-conservative amino acid change located in the Filamin/ABP280 repeat domain (IPR017868) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 248982 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9-fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05). c.4413A>T has been reported in the literature in individuals affected with Cardiomyopathy (Chumakova_2023,vanderMeulen_2022), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (MYBPC3 c.743_746del, p.Asp248Alafs*51), providing supporting evidence for a benign role (Chumakova_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38002985, 36178741). ClinVar contains an entry for this variant (Variation ID: 539450). Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 19, 2022

Phosphorus, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant results in an amino acid substitution of glutamine with histidine at codon 1471 of the FLNC gene. The variant has an entry in ClinVar (539450) NM_001458.5 (FLNC): c.4413A>T (p.Gln1471His) and has occurred in GnomAD with a total MAF of 0.0037% and highest MAF of 0.0081% in the European population. This position is not conserved. In silico functional algorithms agreed, with PolyPhen calling it possibly damaging, and SIFT deleterious, but no functional studies were performed to confirm these predictions. The variant has not occurred in literature associated with disease. Considering that this is a rare variant, whose impact on the protein and association with disease are unknown, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Feb 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1471H variant (also known as c.4413A>T), located in coding exon 25 of the FLNC gene, results from an A to T substitution at nucleotide position 4413. The glutamine at codon 1471 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1471 of the FLNC protein (p.Gln1471His). This variant is present in population databases (rs765435961, gnomAD 0.008%). This missense change has been observed in individual(s) with FLNC-related conditions (PMID: 36178741). ClinVar contains an entry for this variant (Variation ID: 539450). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.22

T;T

MetaSVM

Uncertain

-0.074

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.70

P;P

Vest4

0.27

MutPred

0.48

Gain of methylation at R1474 (P = 0.0474);Gain of methylation at R1474 (P = 0.0474);

MVP

0.68

MPC

0.63

ClinPred

0.39

GERP RS

-2.2

Varity_R

0.23

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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