rs797045934
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000540.3(RYR1):c.3381+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,496 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 Pathogenic (★★).
Frequency
Consequence
NM_000540.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.3381+1G>A | splice_donor_variant | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.3381+1G>A | splice_donor_variant | 5 | NM_000540.3 | A2 | |||
RYR1 | ENST00000355481.8 | c.3381+1G>A | splice_donor_variant | 1 | P4 | ||||
RYR1 | ENST00000594111.1 | n.475G>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
RYR1 | ENST00000599547.6 | c.3381+1G>A | splice_donor_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461496Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727046
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change affects a donor splice site in intron 25 of the RYR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive congenital myopathy (PMID: 20839240, 23553787). ClinVar contains an entry for this variant (Variation ID: 212103). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 28, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at