rs747642919
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001458.5(FLNC):āc.4579A>Gā(p.Ser1527Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1527R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.4579A>G | p.Ser1527Gly | missense_variant, splice_region_variant | 26/48 | ENST00000325888.13 | |
FLNC | NM_001127487.2 | c.4579A>G | p.Ser1527Gly | missense_variant, splice_region_variant | 26/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.4579A>G | p.Ser1527Gly | missense_variant, splice_region_variant | 26/48 | 1 | NM_001458.5 | P3 | |
FLNC | ENST00000346177.6 | c.4579A>G | p.Ser1527Gly | missense_variant, splice_region_variant | 26/47 | 1 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000886 AC: 2AN: 225740Hom.: 0 AF XY: 0.0000163 AC XY: 2AN XY: 122882
GnomAD4 exome AF: 6.90e-7 AC: 1AN: 1450298Hom.: 0 Cov.: 36 AF XY: 0.00000139 AC XY: 1AN XY: 720490
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
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 | Aug 27, 2021 | This sequence change replaces serine with glycine at codon 1527 of the FLNC protein (p.Ser1527Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with FLNC-related conditions. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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