15-33644304-T-G

Variant names:

• chr15-33644304-T-G
• rs183792071
• NM_001036.6:c.3557-7T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001036.6(RYR3):​c.3557-7T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,604,910 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (1 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, intron
• Scores: Splicing: ADA: 0.1227
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.833
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-33644304-T-G is Benign according to our data. Variant chr15-33644304-T-G is described in ClinVar as Benign. ClinVar VariationId is 461906.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.3557-7T>G		splice_region intron	N/A	NP_001027.3
	RYR3	NM_001243996.4		c.3557-7T>G		splice_region intron	N/A	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.3557-7T>G		splice_region intron	N/A	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.3557-7T>G		splice_region intron	N/A	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.3557-7T>G		splice_region intron	N/A	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 46 AN: 235938 AF XY: 0.000133

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000785 AC: 114 AN: 1452594 Hom.: 1 Cov.: 31 AF XY: 0.0000624 AC XY: 45 AN XY: 721550

African (AFR) AF: 0.00285 AC: 95 AN: 33382

American (AMR) AF: 0.000160 AC: 7 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 84240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52824

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5418

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107626

Other (OTH) AF: 0.000166 AC: 10 AN: 60082

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74482

African (AFR) AF: 0.00207 AC: 86 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000735 Hom.: 0

Bravo AF: 0.000763

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.0
DANN	Benign	0.68
PhyloP100		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.060		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: rs183792071; hg19: chr15-33936505;