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GeneBe

15-33859700-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_001036.6(RYR3):c.14268C>T(p.Phe4756=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,611,940 control chromosomes in the GnomAD database, including 1,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.033 ( 157 hom., cov: 32)
Exomes 𝑓: 0.038 ( 1327 hom. )

Consequence

RYR3
NM_001036.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.229
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]
AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-33859700-C-T is Benign according to our data. Variant chr15-33859700-C-T is described in ClinVar as [Benign]. Clinvar id is 461877.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-33859700-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.229 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0326 (4958/152212) while in subpopulation NFE AF= 0.039 (2655/67998). AF 95% confidence interval is 0.0378. There are 157 homozygotes in gnomad4. There are 2657 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 157 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RYR3NM_001036.6 linkuse as main transcriptc.14268C>T p.Phe4756= synonymous_variant 100/104 ENST00000634891.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RYR3ENST00000634891.2 linkuse as main transcriptc.14268C>T p.Phe4756= synonymous_variant 100/1041 NM_001036.6 P4Q15413-1
ENST00000560268.2 linkuse as main transcriptn.70-606G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0326
AC:
4961
AN:
152094
Hom.:
157
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0300
Gnomad ASJ
AF:
0.0331
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.0120
Gnomad FIN
AF:
0.124
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0391
Gnomad OTH
AF:
0.0263
GnomAD3 exomes
AF:
0.0356
AC:
8741
AN:
245636
Hom.:
276
AF XY:
0.0362
AC XY:
4814
AN XY:
133140
show subpopulations
Gnomad AFR exome
AF:
0.00713
Gnomad AMR exome
AF:
0.0221
Gnomad ASJ exome
AF:
0.0305
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0132
Gnomad FIN exome
AF:
0.115
Gnomad NFE exome
AF:
0.0399
Gnomad OTH exome
AF:
0.0474
GnomAD4 exome
AF:
0.0378
AC:
55211
AN:
1459728
Hom.:
1327
Cov.:
32
AF XY:
0.0369
AC XY:
26799
AN XY:
725930
show subpopulations
Gnomad4 AFR exome
AF:
0.00538
Gnomad4 AMR exome
AF:
0.0227
Gnomad4 ASJ exome
AF:
0.0314
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0144
Gnomad4 FIN exome
AF:
0.110
Gnomad4 NFE exome
AF:
0.0395
Gnomad4 OTH exome
AF:
0.0351
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0326
AC:
4958
AN:
152212
Hom.:
157
Cov.:
32
AF XY:
0.0357
AC XY:
2657
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.00722
Gnomad4 AMR
AF:
0.0299
Gnomad4 ASJ
AF:
0.0331
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.0118
Gnomad4 FIN
AF:
0.124
Gnomad4 NFE
AF:
0.0390
Gnomad4 OTH
AF:
0.0265
Alfa
AF:
0.0340
Hom.:
51
Bravo
AF:
0.0260
Asia WGS
AF:
0.00606
AC:
22
AN:
3478

ClinVar

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

Submissions by phenotype

Epileptic encephalopathy Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 15, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.29
Cadd
Benign
4.1
Dann
Benign
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs79305633; hg19: chr15-34151901; COSMIC: COSV66793253; COSMIC: COSV66793253; API