Variant 15-33660308-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6 linkuse as main transcript	c.4507A>T	p.Met1503Leu	missense_variant	34/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2 linkuse as main transcript	c.4507A>T	p.Met1503Leu	missense_variant	34/104	1	NM_001036.6	P4	Q15413-1
RYR3	ENST00000389232.9 linkuse as main transcript	c.4507A>T	p.Met1503Leu	missense_variant	34/104	5		A1
RYR3	ENST00000415757.7 linkuse as main transcript	c.4507A>T	p.Met1503Leu	missense_variant	34/103	2		A2	Q15413-2
RYR3	ENST00000634418.1 linkuse as main transcript	c.4507A>T	p.Met1503Leu	missense_variant	34/102	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000100

AC:

AN:

199142

Hom.:

AF XY:

0.00000936

AC XY:

AN XY:

106874

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000251

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

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

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;.;.;.

MutationTaster

Benign

1.0

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over