rs200944014

Positions:

• chr15-33660349-C-G
• chr15-33660349-C-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.4548C>G​(p.Ser1516Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,591,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1516N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.4548C>G	p.Ser1516Arg	missense_variant	34/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.4548C>G	p.Ser1516Arg	missense_variant	34/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.4548C>G	p.Ser1516Arg	missense_variant	34/104	5		A1
RYR3	ENST00000415757.7	c.4548C>G	p.Ser1516Arg	missense_variant	34/103	2		A2
RYR3	ENST00000634418.1	c.4548C>G	p.Ser1516Arg	missense_variant	34/102	5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 23 AN: 211240 Hom.: 0 AF XY: 0.000132 AC XY: 15 AN XY: 113702

Gnomad AFR exome AF: 0.0000825

Gnomad AMR exome AF: 0.0000652

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000387

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 181 AN: 1439646 Hom.: 0 Cov.: 32 AF XY: 0.000129 AC XY: 92 AN XY: 713586

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000480

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000610

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000911 AC: 11

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

Sep 07, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 530987). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (rs200944014, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1516 of the RYR3 protein (p.Ser1516Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
Polyphen		0.93	P;P;.;.;.
Vest4		0.92
MutPred		0.42		Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);Gain of MoRF binding (P = 0.0311);
MVP		0.94
MPC		0.45
ClinPred		0.43	T
GERP RS		3.9
Varity_R		0.60
gMVP		0.77

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: rs200944014; hg19: chr15-33952550;