rs139249269

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000634891.2(RYR3):ā€‹c.13000A>Gā€‹(p.Asn4334Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00014 ( 0 hom., cov: 33)
Exomes š‘“: 0.000014 ( 0 hom. )

Consequence

RYR3
ENST00000634891.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.137
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.010837048).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RYR3NM_001036.6 linkuse as main transcriptc.13000A>G p.Asn4334Asp missense_variant 90/104 ENST00000634891.2 NP_001027.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RYR3ENST00000634891.2 linkuse as main transcriptc.13000A>G p.Asn4334Asp missense_variant 90/1041 NM_001036.6 ENSP00000489262 P4Q15413-1

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000531
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248918
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135038
show subpopulations
Gnomad AFR exome
AF:
0.000323
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000137
AC:
20
AN:
1461640
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000144
AC:
22
AN:
152346
Hom.:
0
Cov.:
33
AF XY:
0.000174
AC XY:
13
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000529
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000498
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.000514
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 04, 2018This sequence change replaces asparagine with aspartic acid at codon 4334 of the RYR3 protein (p.Asn4334Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs139249269, ExAC 0.06%). This variant has not been reported in the literature in individuals with RYR3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
7.8
DANN
Benign
0.86
DEOGEN2
Uncertain
0.43
T;.;.;.;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.51
T;T;T;T;T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.011
T;T;T;T;T;T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
-0.90
N;.;.;.;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.45
.;N;.;.;.;.
REVEL
Benign
0.17
Sift
Benign
0.48
.;T;.;.;.;.
Sift4G
Benign
0.57
.;.;.;.;.;T
Polyphen
0.0
B;B;.;.;.;.
Vest4
0.064
MVP
0.61
MPC
0.21
ClinPred
0.013
T
GERP RS
-0.23
Varity_R
0.043
gMVP
0.065

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139249269; hg19: chr15-34133047; API