rs1555384709

Variant names:

• chr15-33634666-C-G
• rs1555384709
• NM_001036.6:c.3108C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001036.6(RYR3):​c.3108C>G​(p.Ser1036Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0460
• 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: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.3108C>G	p.Ser1036Arg	missense_variant	Exon 25 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.3108C>G	p.Ser1036Arg	missense_variant	Exon 25 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.3108C>G	p.Ser1036Arg	missense_variant	Exon 25 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.3108C>G	p.Ser1036Arg	missense_variant	Exon 25 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.3108C>G	p.Ser1036Arg	missense_variant	Exon 25 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Apr 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR3-related disease. This sequence change replaces serine with arginine at codon 1036 of the RYR3 protein (p.Ser1036Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.
PhyloP100		0.046
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.3	.;D;D;.;.
REVEL	Pathogenic	0.68
Sift	Benign	0.076	.;T;T;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.83
MutPred		0.68		Loss of phosphorylation at S1036 (P = 0.0145);Loss of phosphorylation at S1036 (P = 0.0145);Loss of phosphorylation at S1036 (P = 0.0145);Loss of phosphorylation at S1036 (P = 0.0145);Loss of phosphorylation at S1036 (P = 0.0145);
MVP		0.97
MPC		0.77
ClinPred		1.0	D
GERP RS		-1.3
Varity_R		0.63
gMVP		0.86
Mutation Taster		=26/74	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: rs1555384709; hg19: chr15-33926867;