dbSNP rs190742260: RYR3:c.1437+8G>A (chr15-33580152-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001036.6(RYR3):c.1437+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,581,280 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 4 hom. )

Consequence

RYR3
NM_001036.6 splice_region, intron

Scores

Splicing: ADA: 0.00001206

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.00

Publications

0 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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen, G2P
congenital myopathy
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

RYR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 15-33580152-G-A is Benign according to our data. Variant chr15-33580152-G-A is described in ClinVar as Benign. ClinVar VariationId is 461879.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.1437+8G>A		splice_region_variant, intron_variant	Intron 13 of 103	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR3	ENST00000634891.2 link	c.1437+8G>A	splice_region_variant, intron_variant	Intron 13 of 103	1	NM_001036.6	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9 link	c.1437+8G>A	splice_region_variant, intron_variant	Intron 13 of 103	5		ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7 link	c.1437+8G>A	splice_region_variant, intron_variant	Intron 13 of 102	2		ENSP00000399610.3	Q15413-2
RYR3	ENST00000634418.1 link	c.1437+8G>A	splice_region_variant, intron_variant	Intron 13 of 101	5		ENSP00000489529.1	A0A0U1RRH1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00258

AC:

505

AN:

195610

AF XY:

0.00206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000798

GnomAD4 exome

AF:

0.000449

AC:

641

AN:

1429070

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

275

AN XY:

708200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32472

American (AMR)

AF:

0.0154

AC:

608

AN:

39376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25350

East Asian (EAS)

AF:

0.000420

AC:

AN:

38066

South Asian (SAS)

AF:

0.00

AC:

AN:

81816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51850

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1095162

Other (OTH)

AF:

0.000186

AC:

AN:

59268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

119

149

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:

0.000637

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41508

American (AMR)

AF:

0.00562

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00154

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000339

Hom.:

Bravo

AF:

0.00127

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epileptic encephalopathy

Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.049

(source)

DANN

Benign

0.62

PhyloP100

-5.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0

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