rs370042010

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001458.5(FLNC):​c.3872G>A​(p.Arg1291His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

FLNC
NM_001458.5 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.080145836).
BP6
Variant 7-128846071-G-A is Benign according to our data. Variant chr7-128846071-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 568679.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BS2
High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNCNM_001458.5 linkc.3872G>A p.Arg1291His missense_variant Exon 22 of 48 ENST00000325888.13 NP_001449.3 Q14315-1Q59H94
FLNCNM_001127487.2 linkc.3872G>A p.Arg1291His missense_variant Exon 22 of 47 NP_001120959.1 Q14315-2Q59H94

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNCENST00000325888.13 linkc.3872G>A p.Arg1291His missense_variant Exon 22 of 48 1 NM_001458.5 ENSP00000327145.8 Q14315-1
FLNCENST00000346177.6 linkc.3872G>A p.Arg1291His missense_variant Exon 22 of 47 1 ENSP00000344002.6 Q14315-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000805
AC:
20
AN:
248382
Hom.:
0
AF XY:
0.000104
AC XY:
14
AN XY:
135052
show subpopulations
Gnomad AFR exome
AF:
0.0000653
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000977
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000102
AC:
149
AN:
1461634
Hom.:
1
Cov.:
34
AF XY:
0.0000990
AC XY:
72
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000998
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000985
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000239
AC:
2
ExAC
AF:
0.0000909
AC:
11
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Jun 27, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FLNC: BP4, BS2 -

Apr 16, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1
May 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R1291H variant (also known as c.3872G>A), located in coding exon 22 of the FLNC gene, results from a G to A substitution at nucleotide position 3872. The arginine at codon 1291 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.080
T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
1.1
L;L
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.75
N;N
REVEL
Benign
0.27
Sift
Benign
0.44
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.015
B;B
Vest4
0.26
MVP
0.55
MPC
0.35
ClinPred
0.025
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.041
gMVP
0.29

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.

Other links and lift over

dbSNP: rs370042010; hg19: chr7-128486125; COSMIC: COSV57953117; COSMIC: COSV57953117; API