rs80354707

Positions:

• chr15-33669349-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000634891.2(RYR3):​c.5620-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,538 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (9 hom., cov: 31)
  • Exomes 𝑓: 0.00063 (15 hom.)
• Consequence: RYR3 ENST00000634891.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1094
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.998

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-33669349-C-G is Benign according to our data. Variant chr15-33669349-C-G is described in ClinVar as [Benign]. Clinvar id is 461931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00669 (1019/152266) while in subpopulation AFR AF= 0.0237 (983/41546). AF 95% confidence interval is 0.0224. There are 9 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.5620-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.5620-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001036.6	ENSP00000489262	P4
RYR3	ENST00000389232.9	c.5620-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000373884	A1
RYR3	ENST00000415757.7	c.5620-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000399610	A2
RYR3	ENST00000634418.1	c.5620-5C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000489529

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1012 AN: 152150 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00153 AC: 381 AN: 249220 Hom.: 4 AF XY: 0.00116 AC XY: 157 AN XY: 135212

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000628 AC: 917 AN: 1461272 Hom.: 15 Cov.: 30 AF XY: 0.000531 AC XY: 386 AN XY: 726934

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00669 AC: 1019 AN: 152266 Hom.: 9 Cov.: 31 AF XY: 0.00653 AC XY: 486 AN XY: 74468

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00757

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

RYR3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.1
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80354707; hg19: chr15-33961550;