15-33861083-A-G

Variant names:

• chr15-33861083-A-G
• rs199553688
• NM_001036.6:c.14370A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001036.6(RYR3):​c.14370A>G​(p.Lys4790Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000915 in 1,584,014 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: RYR3 NM_001036.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.11
• Publications: 1 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]

AVEN (HGNC:13509): (apoptosis and caspase activation inhibitor) Involved in negative regulation of apoptotic process. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259287 (HGNC:58469):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-33861083-A-G is Benign according to our data. Variant chr15-33861083-A-G is described in ClinVar as Benign. ClinVar VariationId is 531162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.11 with no splicing effect.

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.14370A>G	p.Lys4790Lys	synonymous	Exon 102 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.14355A>G	p.Lys4785Lys	synonymous	Exon 101 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.14370A>G	p.Lys4790Lys	synonymous	Exon 102 of 104	ENSP00000489262.1
	RYR3	ENST00000389232.9	TSL:5	c.14367A>G	p.Lys4789Lys	synonymous	Exon 102 of 104	ENSP00000373884.5
	RYR3	ENST00000415757.7	TSL:2	c.14355A>G	p.Lys4785Lys	synonymous	Exon 101 of 103	ENSP00000399610.3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000236 AC: 49 AN: 207428 AF XY: 0.000253

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000338

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000887 AC: 127 AN: 1431714 Hom.: 0 Cov.: 30 AF XY: 0.0000945 AC XY: 67 AN XY: 709006

African (AFR) AF: 0.00 AC: 0 AN: 33032

American (AMR) AF: 0.0000249 AC: 1 AN: 40188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.00131 AC: 51 AN: 38914

South Asian (SAS) AF: 0.000416 AC: 34 AN: 81804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51788

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5730

European-Non Finnish (NFE) AF: 0.0000320 AC: 35 AN: 1095330

Other (OTH) AF: 0.0000842 AC: 5 AN: 59372

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41570

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

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

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000125

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.9
DANN	Benign	0.87
PhyloP100		3.1
Mutation Taster		=99/1	polymorphism

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: rs199553688; hg19: chr15-34153284;