rs79305633

Variant names:

• chr15-33859700-C-T
• rs79305633
• NM_001036.6:c.14268C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001036.6(RYR3):​c.14268C>T​(p.Phe4756Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,611,940 control chromosomes in the GnomAD database, including 1,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (157 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1327 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.229
• 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]

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259287 (HGNC:58469):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 15-33859700-C-T is Benign according to our data. Variant chr15-33859700-C-T is described in ClinVar as Benign. ClinVar VariationId is 461877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.229 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0326 (4958/152212) while in subpopulation NFE AF = 0.039 (2655/67998). AF 95% confidence interval is 0.0378. There are 157 homozygotes in GnomAd4. There are 2657 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 157 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.14268C>T	p.Phe4756Phe	synonymous	Exon 100 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.14253C>T	p.Phe4751Phe	synonymous	Exon 99 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.14268C>T	p.Phe4756Phe	synonymous	Exon 100 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.14265C>T	p.Phe4755Phe	synonymous	Exon 100 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.14253C>T	p.Phe4751Phe	synonymous	Exon 99 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4961 AN: 152094 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.00724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0356 AC: 8741 AN: 245636 AF XY: 0.0362

Gnomad AFR exome AF: 0.00713

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0474

GnomAD4 exome AF: 0.0378 AC: 55211 AN: 1459728 Hom.: 1327 Cov.: 32 AF XY: 0.0369 AC XY: 26799 AN XY: 725930

African (AFR) AF: 0.00538 AC: 180 AN: 33468

American (AMR) AF: 0.0227 AC: 1010 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 820 AN: 26074

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.0144 AC: 1237 AN: 85892

European-Finnish (FIN) AF: 0.110 AC: 5867 AN: 53304

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5764

European-Non Finnish (NFE) AF: 0.0395 AC: 43879 AN: 1110776

Other (OTH) AF: 0.0351 AC: 2118 AN: 60316

GnomAD4 genome AF: 0.0326 AC: 4958 AN: 152212 Hom.: 157 Cov.: 32 AF XY: 0.0357 AC XY: 2657 AN XY: 74432

African (AFR) AF: 0.00722 AC: 300 AN: 41540

American (AMR) AF: 0.0299 AC: 458 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4818

European-Finnish (FIN) AF: 0.124 AC: 1310 AN: 10576

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2655 AN: 67998

Other (OTH) AF: 0.0265 AC: 56 AN: 2116

Alfa AF: 0.0340 Hom.: 51

Bravo AF: 0.0260

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	4.1
DANN	Benign	0.80
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79305633; hg19: chr15-34151901; COSMIC: COSV66793253; COSMIC: COSV66793253;