15-33311056-G-C

Variant names:

• chr15-33311056-G-C
• rs375998723
• NM_001036.6:c.11G>C

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.11G>C​(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000581 in 1,582,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.73

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031689465).
• BP6: Variant 15-33311056-G-C is Benign according to our data. Variant chr15-33311056-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 857441.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6	c.11G>C	p.Gly4Ala	missense_variant	Exon 1 of 104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.11G>C	p.Gly4Ala	missense_variant	Exon 1 of 104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000182 AC: 40 AN: 220298 AF XY: 0.000190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000494

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.0000538 AC: 77 AN: 1430728 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 44 AN XY: 711350

Gnomad4 AFR exome AF: 0.000130 AC: 4 AN: 30878

Gnomad4 AMR exome AF: 0.000895 AC: 37 AN: 41356

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25386

Gnomad4 EAS exome AF: 0.0000832 AC: 3 AN: 36072

Gnomad4 SAS exome AF: 0.0000242 AC: 2 AN: 82516

Gnomad4 FIN exome AF: 0.0000378 AC: 2 AN: 52932

Gnomad4 NFE exome AF: 0.0000218 AC: 24 AN: 1098506

Gnomad4 Remaining exome AF: 0.0000509 AC: 3 AN: 58980

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74326

Gnomad4 AFR AF: 0.000169 AC: 0.000168919 AN: 0.000168919

Gnomad4 AMR AF: 0.000392 AC: 0.000392362 AN: 0.000392362

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293997 AN: 0.0000293997

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000141 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11G>C (p.G4A) alteration is located in exon 1 (coding exon 1) of the RYR3 gene. This alteration results from a G to C substitution at nucleotide position 11, causing the glycine (G) at amino acid position 4 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myopathy 20 Uncertain:1

Jan 29, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epileptic encephalopathy Benign:1

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.25	T;.;.;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.59	T;T;T;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.9	M;M;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.35	.;N;N;.;.
REVEL	Benign	0.27
Sift	Benign	1.0	.;T;T;.;.
Polyphen		0.0	B;B;.;.;.
Vest4		0.15
MVP		0.51
MPC		0.20
ClinPred		0.035	T
GERP RS		-2.5
Varity_R		0.037
gMVP		0.22
Mutation Taster		=79/21	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

Publications

LitVar

Other links and lift over

dbSNP: rs375998723; hg19: chr15-33603257;