15-33311059-G-T

Variant names:

• chr15-33311059-G-T
• rs771419772
• NM_001036.6:c.14G>T

Variant summary

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

The NM_001036.6(RYR3):​c.14G>T​(p.Gly5Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000021 in 1,431,278 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. G5E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.60
• 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: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000309207 (HGNC:):

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.14G>T	p.Gly5Val	missense_variant	Exon 1 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.14G>T	p.Gly5Val	missense_variant	Exon 1 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1431278 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 711606

African (AFR) AF: 0.00 AC: 0 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 41386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25404

East Asian (EAS) AF: 0.00 AC: 0 AN: 36130

South Asian (SAS) AF: 0.00 AC: 0 AN: 82578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1098846

Other (OTH) AF: 0.00 AC: 0 AN: 59006

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	.;D;D;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.014	.;D;D;.;.
Polyphen		0.61	P;P;.;.;.
Vest4		0.60
MVP		0.80
MPC		0.35
ClinPred		0.98	D
GERP RS		3.1
PromoterAI		-0.029	Neutral
Varity_R		0.29
gMVP		0.28
Mutation Taster		=41/59	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: rs771419772; hg19: chr15-33603260;