15-33820785-A-T

Variant names:

• chr15-33820785-A-T
• rs200647737
• NM_001036.6:c.10788A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001036.6(RYR3):​c.10788A>T​(p.Glu3596Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,604,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.09
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039092004).
• BP6: Variant 15-33820785-A-T is Benign according to our data. Variant chr15-33820785-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461831.

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.10788A>T	p.Glu3596Asp	missense	Exon 78 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.10773A>T	p.Glu3591Asp	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.10788A>T	p.Glu3596Asp	missense	Exon 78 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.10785A>T	p.Glu3595Asp	missense	Exon 78 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.10773A>T	p.Glu3591Asp	missense	Exon 77 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000171 AC: 40 AN: 233496 AF XY: 0.000127

Gnomad AFR exome AF: 0.00263

Gnomad AMR exome AF: 0.0000911

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000723 AC: 105 AN: 1452392 Hom.: 0 Cov.: 31 AF XY: 0.0000568 AC XY: 41 AN XY: 721216

African (AFR) AF: 0.00282 AC: 94 AN: 33360

American (AMR) AF: 0.000138 AC: 6 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 83590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107478

Other (OTH) AF: 0.0000832 AC: 5 AN: 60128

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152260 Hom.: 0 Cov.: 31 AF XY: 0.000846 AC XY: 63 AN XY: 74452

African (AFR) AF: 0.00301 AC: 125 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000838 Hom.: 0

Bravo AF: 0.000854

ESP6500AA AF: 0.00317 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000207 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.15
DANN	Benign	0.67
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.28
Sift	Benign	0.46	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.19		Gain of helix (P = 0.132)
MVP		0.73
MPC		0.18
ClinPred		0.022	T
GERP RS		-9.4
Varity_R		0.055
gMVP		0.056
Mutation Taster		=71/29	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: rs200647737; hg19: chr15-34112986; COSMIC: COSV66800428; COSMIC: COSV66800428;