chr15-33548155-G-A

Variant names:

• chr15-33548155-G-A
• rs1555522270
• NM_001036.6:c.766G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.766G>A	p.Ala256Thr	missense_variant	Exon 9 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.766G>A	p.Ala256Thr	missense_variant	Exon 9 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.766G>A	p.Ala256Thr	missense_variant	Exon 9 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.766G>A	p.Ala256Thr	missense_variant	Exon 9 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.766G>A	p.Ala256Thr	missense_variant	Exon 9 of 102	5		ENSP00000489529.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111398

Other (OTH) AF: 0.00 AC: 0 AN: 60308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

May 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	.;N;N;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0090	.;D;D;.;.
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
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs1555522270; hg19: chr15-33840356;