rs115119086

Variant names:

• chr15-33662231-G-A
• rs115119086
• NM_001036.6:c.4701G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-33662231-G-A
• chr15-33662231-G-C
• chr15-33662231-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001036.6(RYR3):​c.4701G>A​(p.Ala1567Ala) 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:4
• Conservation: PhyloP100: -2.44
• Publications: 2 publications found

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]

RYR3 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4701G>A	p.Ala1567Ala	synonymous	Exon 35 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4701G>A	p.Ala1567Ala	synonymous	Exon 35 of 103	NP_001230925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.4701G>A	p.Ala1567Ala	synonymous	Exon 35 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.4701G>A	p.Ala1567Ala	synonymous	Exon 35 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.4701G>A	p.Ala1567Ala	synonymous	Exon 35 of 103	ENSP00000399610.3

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

GnomAD2 exomes AF: 0.000902 AC: 215 AN: 238370 AF XY: 0.000751

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 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

African (AFR) AF: 0.0101 AC: 338 AN: 33380

American (AMR) AF: 0.000545 AC: 24 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 84984

European-Finnish (FIN) AF: 0.0000755 AC: 4 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.000252 AC: 280 AN: 1110000

Other (OTH) AF: 0.000897 AC: 54 AN: 60198

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

African (AFR) AF: 0.00813 AC: 338 AN: 41582

American (AMR) AF: 0.00176 AC: 27 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00339

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)
-	-	1	RYR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.15
DANN	Benign	0.51
PhyloP100		-2.4
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs115119086; hg19: chr15-33954432;