Genetic Variant NM_001036.6:c.*839A>G (chr15-33866065-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001036.6(RYR3):c.*839A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.615 in 154,892 control chromosomes in the GnomAD database, including 31,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 30745 hom., cov: 32)

Exomes 𝑓: 0.73 ( 782 hom. )

Consequence

RYR3
NM_001036.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.91

Publications

42 publications found

Variant links:

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 links:

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]

AVEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 15-33866065-A-G is Benign according to our data. Variant chr15-33866065-A-G is described in ClinVar as Benign. ClinVar VariationId is 706987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.*839A>G		3_prime_UTR_variant	Exon 104 of 104	ENST00000634891.2	NP_001027.3	Q15413-1
AVEN	NM_020371.3 link	c.*548T>C		downstream_gene_variant		ENST00000306730.8	NP_065104.1	Q9NQS1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.*839A>G		3_prime_UTR_variant	Exon 104 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1
AVEN	ENST00000306730.8 link	c.*548T>C		downstream_gene_variant		1	NM_020371.3	ENSP00000306822.3		Q9NQS1

Frequencies

GnomAD3 genomes

AF:

0.613

AC:

93121

AN:

151898

Hom.:

30745

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.764

Gnomad AMR

AF:

0.707

Gnomad ASJ

AF:

0.639

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.566

Gnomad FIN

AF:

0.725

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.631

GnomAD4 exome

AF:

0.726

AC:

2086

AN:

2874

Hom.:

782

Cov.:

AF XY:

0.723

AC XY:

1114

AN XY:

1540

show subpopulations

African (AFR)

AF:

0.389

AC:

AN:

American (AMR)

AF:

0.746

AC:

412

AN:

552

Ashkenazi Jewish (ASJ)

AF:

0.417

AC:

AN:

East Asian (EAS)

AF:

0.588

AC:

AN:

South Asian (SAS)

AF:

0.573

AC:

102

AN:

178

European-Finnish (FIN)

AF:

0.731

AC:

316

AN:

432

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.749

AC:

1156

AN:

1544

Other (OTH)

AF:

0.654

AC:

AN:

104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.613

AC:

93135

AN:

152018

Hom.:

30745

Cov.:

AF XY:

0.613

AC XY:

45542

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.352

AC:

14574

AN:

41414

American (AMR)

AF:

0.708

AC:

10810

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

2220

AN:

3472

East Asian (EAS)

AF:

0.452

AC:

2334

AN:

5168

South Asian (SAS)

AF:

0.566

AC:

2731

AN:

4824

European-Finnish (FIN)

AF:

0.725

AC:

7669

AN:

10578

Middle Eastern (MID)

AF:

0.555

AC:

162

AN:

292

European-Non Finnish (NFE)

AF:

0.745

AC:

50621

AN:

67976

Other (OTH)

AF:

0.625

AC:

1317

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1659

3319

4978

6638

8297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.696

Hom.:

152299

Bravo

AF:

0.600

Asia WGS

AF:

0.497

AC:

1729

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

4.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over