15-33636529-G-T

Position:

• chr15-33636529-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001036.6(RYR3):​c.3535G>T​(p.Ala1179Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,447,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. A1179T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19467923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.3535G>T	p.Ala1179Ser	missense_variant	27/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.3535G>T	p.Ala1179Ser	missense_variant	27/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.3535G>T	p.Ala1179Ser	missense_variant	27/104	5		A1
RYR3	ENST00000415757.7	c.3535G>T	p.Ala1179Ser	missense_variant	27/103	2		A2
RYR3	ENST00000634418.1	c.3535G>T	p.Ala1179Ser	missense_variant	27/102	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447946 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 719358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.76	N;N;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.42	.;N;N;.;.
REVEL	Benign	0.076
Sift	Benign	0.68	.;T;T;.;.
Polyphen		0.28	B;B;.;.;.
Vest4		0.35
MutPred		0.49		Loss of catalytic residue at A1179 (P = 0.0585);Loss of catalytic residue at A1179 (P = 0.0585);Loss of catalytic residue at A1179 (P = 0.0585);Loss of catalytic residue at A1179 (P = 0.0585);Loss of catalytic residue at A1179 (P = 0.0585);
MVP		0.36
MPC		0.33
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368220434; hg19: chr15-33928730;