rs199638420

Positions:

• chr15-33630030-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001036.6(RYR3):​c.2770A>G​(p.Thr924Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,589,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.80

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015210718).
• BP6: Variant 15-33630030-A-G is Benign according to our data. Variant chr15-33630030-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR3	NM_001036.6	c.2770A>G	p.Thr924Ala	missense_variant	22/104	ENST00000634891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR3	ENST00000634891.2	c.2770A>G	p.Thr924Ala	missense_variant	22/104	1	NM_001036.6	P4
RYR3	ENST00000389232.9	c.2770A>G	p.Thr924Ala	missense_variant	22/104	5		A1
RYR3	ENST00000415757.7	c.2770A>G	p.Thr924Ala	missense_variant	22/103	2		A2
RYR3	ENST00000634418.1	c.2770A>G	p.Thr924Ala	missense_variant	22/102	5

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000635 AC: 142 AN: 223724 Hom.: 0 AF XY: 0.000675 AC XY: 81 AN XY: 119978

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.000888

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000448 AC: 644 AN: 1437598 Hom.: 0 Cov.: 26 AF XY: 0.000468 AC XY: 334 AN XY: 713994

Gnomad4 AFR exome AF: 0.000393

Gnomad4 AMR exome AF: 0.000849

Gnomad4 ASJ exome AF: 0.00607

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.000227

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74496

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000710 Hom.: 1

Bravo AF: 0.000684

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.000456 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.2770A>G (p.T924A) alteration is located in exon 22 (coding exon 22) of the RYR3 gene. This alteration results from a A to G substitution at nucleotide position 2770, causing the threonine (T) at amino acid position 924 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2022

- -

RYR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.59
DEOGEN2	Benign	0.33	T;.;.;.;.
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Benign	1.4	L;L;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
Polyphen		0.27	B;P;.;.;.
Vest4		0.41
MVP		0.83
MPC		0.25
ClinPred		0.048	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.31

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: rs199638420; hg19: chr15-33922231;