chr15-33865198-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001036.6(RYR3):c.14585G>A(p.Arg4862His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,416 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. R4862C) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.14585G>A | p.Arg4862His | missense_variant | 104/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.14585G>A | p.Arg4862His | missense_variant | 104/104 | 1 | NM_001036.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151970Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250244Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135662
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461446Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29AN XY: 727048
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151970Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74240
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2020 | 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RYR3-related disease. This variant is present in population databases (rs765872802, ExAC 0.01%). This sequence change replaces arginine with histidine at codon 4862 of the RYR3 protein (p.Arg4862His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 30, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at