rs1217109352

Variant names:

• chr15-33660363-G-C
• rs1217109352
• NM_001036.6:c.4562G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001036.6(RYR3):​c.4562G>C​(p.Trp1521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 1,438,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 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: G2P, PanelApp Australia, ClinGen
• congenital myopathy

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4562G>C	p.Trp1521Ser	missense	Exon 34 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4562G>C	p.Trp1521Ser	missense	Exon 34 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.4562G>C	p.Trp1521Ser	missense	Exon 34 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.4562G>C	p.Trp1521Ser	missense	Exon 34 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.4562G>C	p.Trp1521Ser	missense	Exon 34 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000955 AC: 2 AN: 209370 AF XY: 0.00000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000655

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 7 AN: 1438658 Hom.: 0 Cov.: 32 AF XY: 0.00000561 AC XY: 4 AN XY: 713080

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.0000482 AC: 2 AN: 41494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38440

South Asian (SAS) AF: 0.0000610 AC: 5 AN: 81956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101150

Other (OTH) AF: 0.00 AC: 0 AN: 59510

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		10
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.84		Gain of disorder (P = 0.0011)
MVP		0.97
MPC		0.94
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.87
Mutation Taster		=36/64	disease causing

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: rs1217109352; hg19: chr15-33952564;