rs369246005

chr15-33837844-C-Achr15-33837844-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001036.6(RYR3):c.11864C>A(p.Thr3955Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 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. T3955M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.964

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28792325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.11864C>A	p.Thr3955Lys	missense_variant	89/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.11864C>A	p.Thr3955Lys	missense_variant	89/104	1	NM_001036.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Uncertain	0.74	D;.;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.054
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Uncertain	0.62	T
Polyphen		0.33	B;B;.;.;.
Vest4		0.50
MutPred		0.40		Gain of ubiquitination at T3955 (P = 0.0131);.;.;.;.;
MVP		0.35
MPC		0.23
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.45
gMVP		0.55

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

Other links and lift over

dbSNP: rs369246005; hg19: chr15-34130045;