rs201161868

Variant names:

• chr15-33660348-G-A
• rs201161868
• NM_001036.6:c.4547G>A
• RYR3 p.Ser1516Asn

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_001036.6(RYR3):​c.4547G>A​(p.Ser1516Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,592,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1516R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.76
• Publications: 3 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: PanelApp Australia, ClinGen, G2P
• congenital myopathy

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13389331).
• BP6: Variant 15-33660348-G-A is Benign according to our data. Variant chr15-33660348-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 531029.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.4547G>A	p.Ser1516Asn	missense	Exon 34 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.4547G>A	p.Ser1516Asn	missense	Exon 34 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.4547G>A	p.Ser1516Asn	missense	Exon 34 of 104	ENSP00000489262.1	Q15413-1
	RYR3	ENST00000389232.9	TSL:5	c.4547G>A	p.Ser1516Asn	missense	Exon 34 of 104	ENSP00000373884.5	A0A0X1KG73
	RYR3	ENST00000415757.7	TSL:2	c.4547G>A	p.Ser1516Asn	missense	Exon 34 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000113 AC: 24 AN: 212780 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000373

GnomAD4 exome AF: 0.000166 AC: 239 AN: 1440368 Hom.: 0 Cov.: 32 AF XY: 0.000167 AC XY: 119 AN XY: 713974

African (AFR) AF: 0.0000604 AC: 2 AN: 33090

American (AMR) AF: 0.000240 AC: 10 AN: 41728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 38572

South Asian (SAS) AF: 0.0000853 AC: 7 AN: 82100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51762

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5752

European-Non Finnish (NFE) AF: 0.000181 AC: 199 AN: 1101990

Other (OTH) AF: 0.000268 AC: 16 AN: 59624

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.000393 AC: 6 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000177 Hom.: 0

Bravo AF: 0.000144

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Benign	0.064	T
Varity_R		0.39
gMVP		0.63
Mutation Taster		=50/50

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201161868;

hg19: chr15-33952549;