NM_001036.6:c.4435G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_001036.6(RYR3):​c.4435G>A​(p.Glu1479Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000624 in 1,553,366 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 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

8
10

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.73

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4
Computational evidence support a benign effect (MetaRNN=0.12907642).
BP6
Variant 15-33660236-G-A is Benign according to our data. Variant chr15-33660236-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 531063.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR3NM_001036.6 linkc.4435G>A p.Glu1479Lys missense_variant Exon 34 of 104 ENST00000634891.2 NP_001027.3 Q15413-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR3ENST00000634891.2 linkc.4435G>A p.Glu1479Lys missense_variant Exon 34 of 104 1 NM_001036.6 ENSP00000489262.1 Q15413-1
RYR3ENST00000389232.9 linkc.4435G>A p.Glu1479Lys missense_variant Exon 34 of 104 5 ENSP00000373884.5 A0A0X1KG73
RYR3ENST00000415757.7 linkc.4435G>A p.Glu1479Lys missense_variant Exon 34 of 103 2 ENSP00000399610.3 Q15413-2
RYR3ENST00000634418.1 linkc.4435G>A p.Glu1479Lys missense_variant Exon 34 of 102 5 ENSP00000489529.1 A0A0U1RRH1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000138
AC:
22
AN:
159746
AF XY:
0.000166
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000657
AC:
92
AN:
1401160
Hom.:
1
Cov.:
32
AF XY:
0.0000926
AC XY:
64
AN XY:
691222
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31646
American (AMR)
AF:
0.0000279
AC:
1
AN:
35804
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25206
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35810
South Asian (SAS)
AF:
0.00108
AC:
86
AN:
79280
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49496
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5700
European-Non Finnish (NFE)
AF:
9.26e-7
AC:
1
AN:
1080056
Other (OTH)
AF:
0.0000688
AC:
4
AN:
58162
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152206
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41454
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5184
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.545
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000928
AC:
10
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epileptic encephalopathy Benign:1
Feb 23, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;.;.;.;.
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.13
T;T;T;T;T
MetaSVM
Uncertain
0.72
D
MutationAssessor
Benign
1.8
L;L;.;.;.
PhyloP100
3.7
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-0.56
.;N;N;.;.
REVEL
Uncertain
0.36
Sift
Benign
0.23
.;T;T;.;.
Polyphen
0.13
B;P;.;.;.
Vest4
0.57
MutPred
0.30
Gain of methylation at E1479 (P = 0.0076);Gain of methylation at E1479 (P = 0.0076);Gain of methylation at E1479 (P = 0.0076);Gain of methylation at E1479 (P = 0.0076);Gain of methylation at E1479 (P = 0.0076);
MVP
0.50
MPC
0.21
ClinPred
0.22
T
GERP RS
4.8
Varity_R
0.15
gMVP
0.52
Mutation Taster
=92/8
polymorphism

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

Other links and lift over

dbSNP: rs772565900; hg19: chr15-33952437; API