rs780150644
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001036.6(RYR3):c.1342G>A(p.Ala448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A448A) has been classified as Likely benign.
Frequency
Consequence
NM_001036.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.1342G>A | p.Ala448Thr | missense_variant | 13/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.1342G>A | p.Ala448Thr | missense_variant | 13/104 | 1 | NM_001036.6 | P4 | |
RYR3 | ENST00000389232.9 | c.1342G>A | p.Ala448Thr | missense_variant | 13/104 | 5 | A1 | ||
RYR3 | ENST00000415757.7 | c.1342G>A | p.Ala448Thr | missense_variant | 13/103 | 2 | A2 | ||
RYR3 | ENST00000634418.1 | c.1342G>A | p.Ala448Thr | missense_variant | 13/102 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248728Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 134914
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461472Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30AN XY: 727010
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74270
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces alanine with threonine at codon 448 of the RYR3 protein (p.Ala448Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs780150644, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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