19-38492637-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.6274+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,593,032 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000540.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.6274+1G>A | splice_donor_variant | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.6274+1G>A | splice_donor_variant | 5 | NM_000540.3 | A2 | |||
RYR1 | ENST00000355481.8 | c.6274+1G>A | splice_donor_variant | 1 | P4 | ||||
RYR1 | ENST00000599547.6 | c.6274+1G>A | splice_donor_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151940Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000167 AC: 4AN: 238978Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 129662
GnomAD4 exome AF: 0.0000312 AC: 45AN: 1441092Hom.: 0 Cov.: 36 AF XY: 0.0000363 AC XY: 26AN XY: 716594
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151940Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74242
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 23, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Shillington et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34528764) - |
RYR1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change affects a donor splice site in intron 38 of the RYR1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 34528764). ClinVar contains an entry for this variant (Variation ID: 478250). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 34528764). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Multiminicore myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Aug 28, 2018 | This variant affects the canonical splice donor site of intron 38 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has not been reported in the medical literature to our knowledge. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/265694) and thus is presumed to be rare. Based on the available evidence, the c.6274+1G>A variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at