rs781372766
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001036.6(RYR3):c.13781C>T(p.Ala4594Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. A4594T) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR3 | NM_001036.6 | c.13781C>T | p.Ala4594Val | missense_variant | 96/104 | ENST00000634891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR3 | ENST00000634891.2 | c.13781C>T | p.Ala4594Val | missense_variant | 96/104 | 1 | NM_001036.6 | P4 | |
ENST00000560404.2 | n.602+1177G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249076Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135142
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461478Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 727036
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2023 | The c.13781C>T (p.A4594V) alteration is located in exon 96 (coding exon 96) of the RYR3 gene. This alteration results from a C to T substitution at nucleotide position 13781, causing the alanine (A) at amino acid position 4594 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 461868). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (rs781372766, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4594 of the RYR3 protein (p.Ala4594Val). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at