15-33841871-G-T

Variant names:

Variant summary

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

The NM_001036.6(RYR3):c.13045G>T(p.Asp4349Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,592,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.78

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

RYR3 links:

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=0.04577288).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.13045G>T	p.Asp4349Tyr	missense	Exon 91 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.13030G>T	p.Asp4344Tyr	missense	Exon 90 of 103	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.13045G>T	p.Asp4349Tyr	missense	Exon 91 of 104	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.13042G>T	p.Asp4348Tyr	missense	Exon 91 of 104	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.13030G>T	p.Asp4344Tyr	missense	Exon 90 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000599

AC:

AN:

217014

AF XY:

0.0000429

show subpopulations

Gnomad AFR exome

AF:

0.00103

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:

0.0000340

AC:

AN:

1440100

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

713932

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

33038

American (AMR)

AF:

0.00

AC:

AN:

41354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25590

East Asian (EAS)

AF:

0.00

AC:

AN:

38900

South Asian (SAS)

AF:

0.00

AC:

AN:

82350

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101440

Other (OTH)

AF:

0.0000335

AC:

AN:

59744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000309

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41564

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000800

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00132

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000913

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Uncertain:2

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 4349 of the RYR3 protein (p.Asp4349Tyr). This variant is present in population databases (rs199964506, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RYR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 578077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR3 protein function with a negative predictive value of 80%. 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.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.048

MetaRNN

Benign

0.046

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

1.6

PhyloP100

1.8

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.52

Sift

Benign

0.037

Sift4G

Benign

0.13

Polyphen

0.95

Vest4

0.35

MVP

0.69

MPC

0.23

ClinPred

0.24

GERP RS

5.5

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.28

gMVP

0.39

Mutation Taster

=69/31

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over