rs1217109352

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001036.6(RYR3):c.4562G>C(p.Trp1521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 1,438,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

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 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

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.4562G>C	p.Trp1521Ser	missense_variant	Exon 34 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RYR3	ENST00000634891.2 link	c.4562G>C	p.Trp1521Ser	missense_variant	Exon 34 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9 link	c.4562G>C	p.Trp1521Ser	missense_variant	Exon 34 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7 link	c.4562G>C	p.Trp1521Ser	missense_variant	Exon 34 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1 link	c.4562G>C	p.Trp1521Ser	missense_variant	Exon 34 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000955

AC:

AN:

209370

AF XY:

0.00000887

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000655

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:

0.00000487

AC:

AN:

1438658

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

713080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.0000482

AC:

AN:

41494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

38440

South Asian (SAS)

AF:

0.0000610

AC:

AN:

81956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101150

Other (OTH)

AF:

0.00

AC:

AN:

59510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan with serine at codon 1521 of the RYR3 protein (p.Trp1521Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;.;.;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;M;.;.;.

PhyloP100

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.0

.;D;D;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;D;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.

Vest4

0.92

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.87

Mutation Taster

=36/64

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over