dbSNP rs377360254: RYR3:p.Ser1477Arg (chr15-33660232-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001036.6(RYR3):c.4431T>A(p.Ser1477Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.261

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

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.4431T>A	p.Ser1477Arg	missense	Exon 34 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4431T>A	p.Ser1477Arg	missense	Exon 34 of 103	NP_001230925.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.4431T>A	p.Ser1477Arg	missense	Exon 34 of 104	ENSP00000489262.1
RYR3	ENST00000389232.9	TSL:5	c.4431T>A	p.Ser1477Arg	missense	Exon 34 of 104	ENSP00000373884.5
RYR3	ENST00000415757.7	TSL:2	c.4431T>A	p.Ser1477Arg	missense	Exon 34 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000628

AC:

AN:

159268

AF XY:

0.0000119

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000910

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

Eigen

Benign

0.025

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.4

PhyloP100

0.26

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0080

Polyphen

0.64

Vest4

0.97

MutPred

0.21

Loss of ubiquitination at K1480 (P = 0.0343)

MVP

0.96

MPC

0.55

ClinPred

0.97

GERP RS

1.2

Varity_R

0.62

gMVP

0.92

Mutation Taster

=48/52

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over