rs74005974

chr15-33728885-G-Achr15-33728885-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001036.6(RYR3):c.7062G>A(p.Ala2354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,640 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (39 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 15-33728885-G-A is Benign according to our data. Variant chr15-33728885-G-A is described in ClinVar as [Benign]. Clinvar id is 461944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1682/152276) while in subpopulation AFR AF= 0.0325 (1349/41548). AF 95% confidence interval is 0.031. There are 25 homozygotes in gnomad4. There are 791 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.7062G>A	p.Ala2354=	synonymous_variant	47/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.7062G>A	p.Ala2354=	synonymous_variant	47/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1683 AN: 152158 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00334

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00472 AC: 1164 AN: 246510 Hom.: 9 AF XY: 0.00442 AC XY: 591 AN XY: 133750

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000699

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00277

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00520

GnomAD4 exome AF: 0.00353 AC: 5151 AN: 1460364 Hom.: 39 Cov.: 31 AF XY: 0.00347 AC XY: 2522 AN XY: 726322

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.00514

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.0110 AC: 1682 AN: 152276 Hom.: 25 Cov.: 33 AF XY: 0.0106 AC XY: 791 AN XY: 74470

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00334

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00683 Hom.: 3

Bravo AF: 0.0121

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	2.3
Dann	Benign	0.69

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: rs74005974; hg19: chr15-34021086; COSMIC: COSV101213625;