NM_001036.6:c.1073T>A

Variant names:

• chr15-33562937-T-A
• rs2304380
• NM_001036.6:c.1073T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001036.6(RYR3):​c.1073T>A​(p.Ile358Lys) variant causes a missense change. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I358T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.19
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.1073T>A	p.Ile358Lys	missense_variant	Exon 11 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.1073T>A	p.Ile358Lys	missense_variant	Exon 11 of 104	1	NM_001036.6	ENSP00000489262.1
RYR3	ENST00000389232.9	c.1073T>A	p.Ile358Lys	missense_variant	Exon 11 of 104	5		ENSP00000373884.5
RYR3	ENST00000415757.7	c.1073T>A	p.Ile358Lys	missense_variant	Exon 11 of 103	2		ENSP00000399610.3
RYR3	ENST00000634418.1	c.1073T>A	p.Ile358Lys	missense_variant	Exon 11 of 102	5		ENSP00000489529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D;.;.;.;.
Eigen	Benign	-0.030
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.080	D
MutationAssessor	Benign	0.55	N;N;.;.;.
PhyloP100		6.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.0	.;D;D;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0080	.;D;D;.;.
Polyphen		0.0010	B;B;.;.;.
Vest4		0.52
MutPred		0.85		Gain of catalytic residue at I358 (P = 0.0342);Gain of catalytic residue at I358 (P = 0.0342);Gain of catalytic residue at I358 (P = 0.0342);Gain of catalytic residue at I358 (P = 0.0342);Gain of catalytic residue at I358 (P = 0.0342);
MVP		0.48
MPC		0.36
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.30
gMVP		0.60
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2304380; hg19: chr15-33855138;