rs115119086

chr15-33662231-G-Achr15-33662231-G-Cchr15-33662231-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):c.4701G>A(p.Ala1567=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,609,062 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1567A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.44

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 15-33662231-G-A is Benign according to our data. Variant chr15-33662231-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 461917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.4701G>A	p.Ala1567=	synonymous_variant	35/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.4701G>A	p.Ala1567=	synonymous_variant	35/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.4701G>A	p.Ala1567=	synonymous_variant	35/104	5		A1
RYR3	ENST00000415757.7	c.4701G>A	p.Ala1567=	synonymous_variant	35/103	2		A2
RYR3	ENST00000634418.1	c.4701G>A	p.Ala1567=	synonymous_variant	35/102	5

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 396 AN: 152216 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00803

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.000367

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.000902 AC: 215 AN: 238370 Hom.: 0 AF XY: 0.000751 AC XY: 97 AN XY: 129128

Gnomad AFR exome AF: 0.00896

Gnomad AMR exome AF: 0.000478

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000690

Gnomad FIN exome AF: 0.0000964

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000482 AC: 702 AN: 1456728 Hom.: 0 Cov.: 31 AF XY: 0.000428 AC XY: 310 AN XY: 724046

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.000545

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.0000755

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.000897

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152334 Hom.: 4 Cov.: 33 AF XY: 0.00234 AC XY: 174 AN XY: 74502

Gnomad4 AFR AF: 0.00813

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00339

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

RYR3: BP4, BP7 -

RYR3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.15
Dann	Benign	0.51

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: rs115119086; hg19: chr15-33954432;