rs377266014
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001036.6(RYR3):c.4129C>T(p.Arg1377Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,344 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. R1377Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001036.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.4129C>T | p.Arg1377Trp | missense_variant | 31/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.4129C>T | p.Arg1377Trp | missense_variant | 31/104 | 1 | NM_001036.6 | P4 | |
RYR3 | ENST00000389232.9 | c.4129C>T | p.Arg1377Trp | missense_variant | 31/104 | 5 | A1 | ||
RYR3 | ENST00000415757.7 | c.4129C>T | p.Arg1377Trp | missense_variant | 31/103 | 2 | A2 | ||
RYR3 | ENST00000634418.1 | c.4129C>T | p.Arg1377Trp | missense_variant | 31/102 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247336Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134404
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460244Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726422
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74284
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2017 | This sequence change replaces arginine with tryptophan at codon 1377 of the RYR3 protein (p.Arg1377Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RYR3-related disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at