15-33784441-G-T

Variant names:

• chr15-33784441-G-T
• rs735612
• NM_001036.6:c.9269-1221G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001036.6(RYR3):​c.9269-1221G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 152,170 control chromosomes in the GnomAD database, including 27,400 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (27400 hom., cov: 34)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.902
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.9269-1221G>T		intron_variant	Intron 65 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.9269-1221G>T		intron_variant	Intron 65 of 103	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89709 AN: 152052 Hom.: 27386 Cov.: 34

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.653

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.620

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.590 AC: 89764 AN: 152170 Hom.: 27400 Cov.: 34 AF XY: 0.597 AC XY: 44412 AN XY: 74380

African (AFR) AF: 0.461 AC: 19149 AN: 41508

American (AMR) AF: 0.532 AC: 8137 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2154 AN: 3470

East Asian (EAS) AF: 0.955 AC: 4951 AN: 5184

South Asian (SAS) AF: 0.790 AC: 3810 AN: 4822

European-Finnish (FIN) AF: 0.681 AC: 7215 AN: 10588

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42374 AN: 67990

Other (OTH) AF: 0.622 AC: 1315 AN: 2114

Alfa AF: 0.599 Hom.: 37569

Bravo AF: 0.569

Asia WGS AF: 0.842 AC: 2925 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.54
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

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: rs735612; hg19: chr15-34076642;