rs567024433
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001036.6(RYR3):āc.13860C>Gā(p.Asn4620Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000957 in 1,567,352 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 ).
Frequency
Consequence
NM_001036.6 missense, splice_region
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.13860C>G | p.Asn4620Lys | missense_variant, splice_region_variant | 97/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.13860C>G | p.Asn4620Lys | missense_variant, splice_region_variant | 97/104 | 1 | NM_001036.6 | P4 | |
ENST00000560404.2 | n.602+392G>C | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152052Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 182996Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 97902
GnomAD4 exome AF: 0.00000989 AC: 14AN: 1415300Hom.: 0 Cov.: 30 AF XY: 0.00000714 AC XY: 5AN XY: 700382
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152052Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74248
ClinVar
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 24, 2021 | 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 (rs567024433, ExAC 0.007%). This sequence change replaces asparagine with lysine at codon 4620 of the RYR3 protein (p.Asn4620Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at