rs74005691

chr15-33580080-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001036.6(RYR3):c.1373G>A(p.Arg458Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,613,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.21

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00508824).
• BP6: Variant 15-33580080-G-A is Benign according to our data. Variant chr15-33580080-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.1373G>A	p.Arg458Gln	missense_variant	13/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.1373G>A	p.Arg458Gln	missense_variant	13/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.1373G>A	p.Arg458Gln	missense_variant	13/104	5		A1
RYR3	ENST00000415757.7	c.1373G>A	p.Arg458Gln	missense_variant	13/103	2		A2
RYR3	ENST00000634418.1	c.1373G>A	p.Arg458Gln	missense_variant	13/102	5

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000428 AC: 106 AN: 247862 Hom.: 0 AF XY: 0.000528 AC XY: 71 AN XY: 134454

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.00187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461242 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 205 AN XY: 726868

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74440

Gnomad4 AFR AF: 0.00258

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000982

ESP6500AA AF: 0.00204 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

RYR3: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.92
DEOGEN2	Uncertain	0.43	T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.60	N;N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
Polyphen		0.0	B;B;.;.;.
Vest4		0.051
MVP		0.33
MPC		0.21
ClinPred		0.014	T
GERP RS		-3.3
Varity_R		0.025
gMVP		0.099

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: rs74005691; hg19: chr15-33872281; COSMIC: COSV66780888;