rs774163504

chr15-33788388-G-Achr15-33788388-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001036.6(RYR3):c.9760G>A(p.Glu3254Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.9760G>A	p.Glu3254Lys	missense_variant	67/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.9760G>A	p.Glu3254Lys	missense_variant	67/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249100 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135138

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727124

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.6	L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Polyphen		0.61	P;D;.;.;.
Vest4		0.94
MutPred		0.53		Gain of methylation at E3254 (P = 0.0086);Gain of methylation at E3254 (P = 0.0086);.;Gain of methylation at E3254 (P = 0.0086);.;
MVP		0.80
MPC		0.24
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.43
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs774163504; hg19: chr15-34080589; COSMIC: COSV66791228;