Genetic Variant RYR3:p.Met1503Leu (chr15-33660308-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001036.6(RYR3):c.4507A>T(p.Met1503Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,429,130 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1503I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.36

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.4507A>T	p.Met1503Leu	missense_variant	Exon 34 of 104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR3	ENST00000634891.2 link	c.4507A>T	p.Met1503Leu	missense_variant	Exon 34 of 104	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.4507A>T	p.Met1503Leu	missense_variant	Exon 34 of 104	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.4507A>T	p.Met1503Leu	missense_variant	Exon 34 of 103	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.4507A>T	p.Met1503Leu	missense_variant	Exon 34 of 102	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000100

AC:

AN:

199142

AF XY:

0.00000936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1429130

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32774

American (AMR)

AF:

0.0000251

AC:

AN:

39842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

37798

South Asian (SAS)

AF:

0.00

AC:

AN:

81042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1095926

Other (OTH)

AF:

0.00

AC:

AN:

59252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.45

T;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.66

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.9

L;L;.;.;.

PhyloP100

6.4

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.0

.;N;N;.;.

REVEL

Pathogenic

0.67

Sift

Benign

0.13

.;T;T;.;.

Polyphen

0.0080

B;P;.;.;.

Vest4

0.69

MutPred

0.40

Loss of catalytic residue at M1503 (P = 0.0186);Loss of catalytic residue at M1503 (P = 0.0186);Loss of catalytic residue at M1503 (P = 0.0186);Loss of catalytic residue at M1503 (P = 0.0186);Loss of catalytic residue at M1503 (P = 0.0186);

MVP

0.75

MPC

0.17

ClinPred

0.48

GERP RS

4.8

Varity_R

0.38

gMVP

0.47

Mutation Taster

=75/25

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over