rs773752097

Variant names:

• chr15-33827280-G-A
• rs773752097
• NM_001036.6:c.11327G>A

Variant summary

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

The NM_001036.6(RYR3):​c.11327G>A​(p.Arg3776His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,552,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3776C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81
• Publications: 1 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 0 ACMG points.

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.11327G>A	p.Arg3776His	missense	Exon 85 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.11312G>A	p.Arg3771His	missense	Exon 84 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.11327G>A	p.Arg3776His	missense	Exon 85 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.11324G>A	p.Arg3775His	missense	Exon 85 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.11312G>A	p.Arg3771His	missense	Exon 84 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 22 AN: 158052 AF XY: 0.000144

Gnomad AFR exome AF: 0.000120

Gnomad AMR exome AF: 0.000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000647

Gnomad NFE exome AF: 0.0000959

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000878 AC: 123 AN: 1400794 Hom.: 0 Cov.: 31 AF XY: 0.0000810 AC XY: 56 AN XY: 691030

African (AFR) AF: 0.0000316 AC: 1 AN: 31626

American (AMR) AF: 0.000503 AC: 18 AN: 35814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25208

East Asian (EAS) AF: 0.00 AC: 0 AN: 35800

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79282

European-Finnish (FIN) AF: 0.0000607 AC: 3 AN: 49404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000870 AC: 94 AN: 1079856

Other (OTH) AF: 0.000103 AC: 6 AN: 58100

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74420

African (AFR) AF: 0.0000963 AC: 4 AN: 41544

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

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	0.68
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.98
MPC		0.82
ClinPred		0.49	T
GERP RS		5.4
Varity_R		0.79
gMVP		0.62
Mutation Taster		=18/82	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: rs773752097; hg19: chr15-34119481; COSMIC: COSV107491075; COSMIC: COSV107491075;