Genetic Variant NM_001036.6:c.815+6G>A (chr15-33548210-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001036.6(RYR3):c.815+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000057 in 1,403,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

RYR3
NM_001036.6 splice_region, intron

Scores

Splicing: ADA: 0.002170

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.815+6G>A		splice_region_variant, intron_variant	Intron 9 of 103	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR3	ENST00000634891.2 link	c.815+6G>A	splice_region_variant, intron_variant	Intron 9 of 103	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.815+6G>A	splice_region_variant, intron_variant	Intron 9 of 103	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.815+6G>A	splice_region_variant, intron_variant	Intron 9 of 102	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.815+6G>A	splice_region_variant, intron_variant	Intron 9 of 101	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000211

AC:

AN:

236654

AF XY:

0.0000234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000570

AC:

AN:

1403528

Hom.:

Cov.:

AF XY:

0.00000856

AC XY:

AN XY:

700984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31944

American (AMR)

AF:

0.00

AC:

AN:

43052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.000101

AC:

AN:

39432

South Asian (SAS)

AF:

0.00

AC:

AN:

83370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00000376

AC:

AN:

1063136

Other (OTH)

AF:

0.00

AC:

AN:

58390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Dec 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with RYR3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change falls in intron 9 of the RYR3 gene. It does not directly change the encoded amino acid sequence of the RYR3 protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 577384). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0022

dbscSNV1_RF

Benign

0.022

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

Publications

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NM_001036.6:c.815+6G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over