NM_001036.6:c.280-12625G>A

Variant names:

• chr15-33517967-G-A
• rs6495130
• NM_001036.6:c.280-12625G>A

Variant summary

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

The NM_001036.6(RYR3):​c.280-12625G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 152,032 control chromosomes in the GnomAD database, including 8,904 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 0.33 (8904 hom., cov: 32)
• Consequence: RYR3 NM_001036.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 6 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.280-12625G>A		intron_variant	Intron 3 of 103	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.280-12625G>A		intron_variant	Intron 3 of 103	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.280-12625G>A		intron_variant	Intron 3 of 103	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.280-12625G>A		intron_variant	Intron 3 of 102	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.280-12625G>A		intron_variant	Intron 3 of 101	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49688 AN: 151912 Hom.: 8893 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.327 AC: 49731 AN: 152032 Hom.: 8904 Cov.: 32 AF XY: 0.318 AC XY: 23610 AN XY: 74302

African (AFR) AF: 0.422 AC: 17490 AN: 41454

American (AMR) AF: 0.244 AC: 3724 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5182

South Asian (SAS) AF: 0.144 AC: 693 AN: 4820

European-Finnish (FIN) AF: 0.313 AC: 3303 AN: 10548

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22401 AN: 67960

Other (OTH) AF: 0.310 AC: 657 AN: 2116

Alfa AF: 0.323 Hom.: 28052

Bravo AF: 0.325

Asia WGS AF: 0.0900 AC: 313 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.66
DANN	Benign	0.65
PhyloP100		-0.48
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: rs6495130; hg19: chr15-33810168;