rs754224673
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001458.5(FLNC):āc.4660A>Cā(p.Ile1554Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1554T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4660A>C | p.Ile1554Leu | missense_variant | 27/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4660A>C | p.Ile1554Leu | missense_variant | 27/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4660A>C | p.Ile1554Leu | missense_variant | 27/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4660A>C | p.Ile1554Leu | missense_variant | 27/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 248640Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 134998
GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461194Hom.: 0 Cov.: 34 AF XY: 0.0000702 AC XY: 51AN XY: 726960
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 539376; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 31, 2023 | The p.I1554L variant (also known as c.4660A>C), located in coding exon 27 of the FLNC gene, results from an A to C substitution at nucleotide position 4660. The isoleucine at codon 1554 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not 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 | Invitae | Sep 24, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1554 of the FLNC protein (p.Ile1554Leu). This variant is present in population databases (rs754224673, gnomAD 0.009%). 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: 539376). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at