rs771464102
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000540.3(RYR1):c.1423A>T(p.Ser475Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S475R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.1423A>T | p.Ser475Cys | missense_variant | 13/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1423A>T | p.Ser475Cys | missense_variant | 13/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1423A>T | p.Ser475Cys | missense_variant | 13/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1423A>T | p.Ser475Cys | missense_variant, NMD_transcript_variant | 13/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247892Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134714
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461430Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727048
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74244
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | RYR1: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 05, 2019 | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 17, 2022 | 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 581618). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs771464102, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 475 of the RYR1 protein (p.Ser475Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at