15-33841953-G-T

Variant names:

• chr15-33841953-G-T
• rs201791791
• NM_001036.6:c.13127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001036.6(RYR3):​c.13127G>T​(p.Arg4376Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,449,506 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4376W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 9 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.13127G>T	p.Arg4376Leu	missense	Exon 91 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.13112G>T	p.Arg4371Leu	missense	Exon 90 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.13127G>T	p.Arg4376Leu	missense	Exon 91 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.13124G>T	p.Arg4375Leu	missense	Exon 91 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.13112G>T	p.Arg4371Leu	missense	Exon 90 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000438 AC: 1 AN: 228284 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449506 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719702

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 83764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52496

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

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106050

Other (OTH) AF: 0.00 AC: 0 AN: 59956

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.51
Sift	Benign	0.42	T
Sift4G	Benign	0.39	T
Polyphen		0.11	B
Vest4		0.56
MutPred		0.53		Loss of solvent accessibility (P = 0.0052)
MVP		0.78
MPC		0.53
ClinPred		0.85	D
GERP RS		5.3
PromoterAI		-0.0072	Neutral
Varity_R		0.24
gMVP		0.38
Mutation Taster		=85/15	polymorphism

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: rs201791791; hg19: chr15-34134154;