rs532872913
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001036.6(RYR3):āc.2785A>Gā(p.Thr929Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,576,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. T929T) has been classified as Likely benign.
Frequency
Consequence
NM_001036.6 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 |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.2785A>G | p.Thr929Ala | missense_variant, splice_region_variant | 23/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.2785A>G | p.Thr929Ala | missense_variant, splice_region_variant | 23/104 | 1 | NM_001036.6 | P4 | |
RYR3 | ENST00000389232.9 | c.2785A>G | p.Thr929Ala | missense_variant, splice_region_variant | 23/104 | 5 | A1 | ||
RYR3 | ENST00000415757.7 | c.2785A>G | p.Thr929Ala | missense_variant, splice_region_variant | 23/103 | 2 | A2 | ||
RYR3 | ENST00000634418.1 | c.2785A>G | p.Thr929Ala | missense_variant, splice_region_variant | 23/102 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000150 AC: 3AN: 200336Hom.: 0 AF XY: 0.0000188 AC XY: 2AN XY: 106646
GnomAD4 exome AF: 0.0000126 AC: 18AN: 1424122Hom.: 0 Cov.: 29 AF XY: 0.0000156 AC XY: 11AN XY: 705200
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 19, 2018 | This sequence change replaces threonine with alanine at codon 929 of the RYR3 protein (p.Thr929Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR3-related disease. 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. 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