rs74005978

chr15-33738442-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001036.6(RYR3):c.7516-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,610,476 control chromosomes in the GnomAD database, including 45 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 0.0089 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (24 hom.)
• Consequence: RYR3 NM_001036.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002680
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.619

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-33738442-C-T is Benign according to our data. Variant chr15-33738442-C-T is described in ClinVar as [Benign]. Clinvar id is 461950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00893 (1360/152284) while in subpopulation AFR AF= 0.0316 (1313/41550). AF 95% confidence interval is 0.0302. There are 21 homozygotes in gnomad4. There are 631 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.7516-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.7516-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1363 AN: 152166 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.00621

GnomAD3 exomes AF: 0.00222 AC: 539 AN: 242830 Hom.: 6 AF XY: 0.00183 AC XY: 241 AN XY: 131518

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000916 AC: 1336 AN: 1458192 Hom.: 24 Cov.: 31 AF XY: 0.000795 AC XY: 576 AN XY: 724880

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000819

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00893 AC: 1360 AN: 152284 Hom.: 21 Cov.: 32 AF XY: 0.00848 AC XY: 631 AN XY: 74450

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00561 Hom.: 2

Bravo AF: 0.0106

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.0
Dann	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0080
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

Publications

LitVar

Other links and lift over

dbSNP: rs74005978; hg19: chr15-34030643;