rs575029619

chr15-33785988-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001036.6(RYR3):c.9589+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,545,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: RYR3 NM_001036.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001532
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.158

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-33785988-G-A is Benign according to our data. Variant chr15-33785988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 531085.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.9589+6G>A		splice_donor_region_variant, intron_variant		ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.9589+6G>A		splice_donor_region_variant, intron_variant		1	NM_001036.6	P4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000494 AC: 97 AN: 196544 Hom.: 1 AF XY: 0.000650 AC XY: 68 AN XY: 104614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000180

Gnomad SAS exome AF: 0.00463

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.000642

GnomAD4 exome AF: 0.000273 AC: 380 AN: 1393036 Hom.: 1 Cov.: 30 AF XY: 0.000390 AC XY: 267 AN XY: 684044

Gnomad4 AFR exome AF: 0.0000629

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000453

Gnomad4 EAS exome AF: 0.0000774

Gnomad4 SAS exome AF: 0.00443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000233

Gnomad4 OTH exome AF: 0.000226

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.0000453

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.12
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.018
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: rs575029619; hg19: chr15-34078189;