rs373573447

Positions:

chr7-128845145-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The ENST00000325888.13(FLNC):c.3680C>T(p.Thr1227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,920 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

FLNC
ENST00000325888.13 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.69

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.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.30201876).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLNC	NM_001458.5 linkuse as main transcript	c.3680C>T	p.Thr1227Ile	missense_variant	21/48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2 linkuse as main transcript	c.3680C>T	p.Thr1227Ile	missense_variant	21/47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13 linkuse as main transcript	c.3680C>T	p.Thr1227Ile	missense_variant	21/48	1	NM_001458.5	ENSP00000327145	P3	Q14315-1
FLNC	ENST00000346177.6 linkuse as main transcript	c.3680C>T	p.Thr1227Ile	missense_variant	21/47	1		ENSP00000344002	A1	Q14315-2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000322

AC:

AN:

248704

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135050

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:

0.0000623

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000423

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000620

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30418145) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The p.T1227I variant (also known as c.3680C>T), located in coding exon 21 of the FLNC gene, results from a C to T substitution at nucleotide position 3680. The threonine at codon 1227 is replaced by isoleucine, an amino acid with similar properties. This variant was reported in two individuals with hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Ader F et al. Med Sci (Paris), 2018 Nov;34 Hors série n°2:39-41). This amino acid position is well conserved in available vertebrate species. 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

Oct 22, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1227 of the FLNC protein (p.Thr1227Ile). This variant is present in population databases (rs373573447, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30418145). ClinVar contains an entry for this variant (Variation ID: 539444). Advanced 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 at Invitae 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

0.089

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

0.0035

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.072

T;T

Polyphen

0.020

B;B

Vest4

0.43

MVP

0.50

MPC

0.42

ClinPred

0.20

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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