15-33820803-A-T

Variant names:

• chr15-33820803-A-T
• rs118124507
• NM_001036.6:c.10806A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001036.6(RYR3):​c.10806A>T​(p.Lys3602Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,866 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K3602K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16247556).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.10806A>T	p.Lys3602Asn	missense	Exon 78 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.10791A>T	p.Lys3597Asn	missense	Exon 77 of 103	NP_001230925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	ENST00000634891.2	TSL:1 MANE Select	c.10806A>T	p.Lys3602Asn	missense	Exon 78 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.10803A>T	p.Lys3601Asn	missense	Exon 78 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.10791A>T	p.Lys3597Asn	missense	Exon 77 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444866 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 716862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33208

American (AMR) AF: 0.00 AC: 0 AN: 42428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 82554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103398

Other (OTH) AF: 0.00 AC: 0 AN: 59880

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.72
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.39
Sift	Benign	0.43	T
Polyphen		0.61	P
Vest4		0.35
MutPred		0.20		Loss of ubiquitination at K3602 (P = 0.0059)
MVP		0.90
MPC		0.26
ClinPred		0.83	D
GERP RS		-0.80
Varity_R		0.28
gMVP		0.20
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs118124507; hg19: chr15-34113004;