rs10519837

Variant names:

• chr15-33615753-A-G
• rs10519837
• NM_001036.6:c.2357+2378A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001036.6(RYR3):​c.2357+2378A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 152,088 control chromosomes in the GnomAD database, including 7,442 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7442 hom., cov: 32)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.433
• Publications: 3 publications found

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]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.2357+2378A>G		intron_variant	Intron 19 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.2357+2378A>G		intron_variant	Intron 19 of 103	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.2357+2378A>G		intron_variant	Intron 19 of 103	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.2357+2378A>G		intron_variant	Intron 19 of 102	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.2357+2378A>G		intron_variant	Intron 19 of 101	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44721 AN: 151970 Hom.: 7450 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.00676

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.327

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.294 AC: 44712 AN: 152088 Hom.: 7442 Cov.: 32 AF XY: 0.291 AC XY: 21645 AN XY: 74356

African (AFR) AF: 0.182 AC: 7546 AN: 41486

American (AMR) AF: 0.278 AC: 4249 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1633 AN: 3468

East Asian (EAS) AF: 0.00678 AC: 35 AN: 5166

South Asian (SAS) AF: 0.204 AC: 983 AN: 4810

European-Finnish (FIN) AF: 0.346 AC: 3652 AN: 10556

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25491 AN: 67988

Other (OTH) AF: 0.322 AC: 681 AN: 2114

Alfa AF: 0.358 Hom.: 16832

Bravo AF: 0.285

Asia WGS AF: 0.101 AC: 353 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.85
DANN	Benign	0.53
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10519837; hg19: chr15-33907954;