rs1555522270

chr15-33548155-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001036.6(RYR3):c.766G>A(p.Ala256Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.766G>A	p.Ala256Thr	missense_variant	9/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.766G>A	p.Ala256Thr	missense_variant	9/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.766G>A	p.Ala256Thr	missense_variant	9/104	5		A1
RYR3	ENST00000415757.7	c.766G>A	p.Ala256Thr	missense_variant	9/103	2		A2
RYR3	ENST00000634418.1	c.766G>A	p.Ala256Thr	missense_variant	9/102	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460446 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726372

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 07, 2018

This sequence change replaces alanine with threonine at codon 256 of the RYR3 protein (p.Ala256Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	2.0	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
Polyphen		0.14	B;P;.;.;.
Vest4		0.48
MutPred		0.50		Gain of phosphorylation at A256 (P = 0.0333);Gain of phosphorylation at A256 (P = 0.0333);Gain of phosphorylation at A256 (P = 0.0333);Gain of phosphorylation at A256 (P = 0.0333);Gain of phosphorylation at A256 (P = 0.0333);
MVP		0.64
MPC		0.32
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555522270; hg19: chr15-33840356;