dbSNP rs79305633: RYR3:p.Phe4756Phe (chr15-33859700-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001036.6(RYR3):c.14268C>T(p.Phe4756Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,611,940 control chromosomes in the GnomAD database, including 1,484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 157 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1327 hom. )

Consequence

RYR3
NM_001036.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.229

Publications

2 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:

ENSG00000259287 (HGNC:58469):

ENSG00000259287 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

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

BP6

Variant 15-33859700-C-T is Benign according to our data. Variant chr15-33859700-C-T is described in ClinVar as Benign. ClinVar VariationId is 461877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.229 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0326 (4958/152212) while in subpopulation NFE AF = 0.039 (2655/67998). AF 95% confidence interval is 0.0378. There are 157 homozygotes in GnomAd4. There are 2657 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 157 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR3	NM_001036.6 link	c.14268C>T	p.Phe4756Phe	synonymous_variant	Exon 100 of 104	ENST00000634891.2	NP_001027.3	Q15413-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2 link	c.14268C>T	p.Phe4756Phe	synonymous_variant	Exon 100 of 104	1	NM_001036.6	ENSP00000489262.1		Q15413-1

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4961

AN:

152094

Hom.:

157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0391

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0356

AC:

8741

AN:

245636

AF XY:

0.0362

show subpopulations

Gnomad AFR exome

AF:

0.00713

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.0305

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.0399

Gnomad OTH exome

AF:

0.0474

GnomAD4 exome

AF:

0.0378

AC:

55211

AN:

1459728

Hom.:

1327

Cov.:

AF XY:

0.0369

AC XY:

26799

AN XY:

725930

show subpopulations

African (AFR)

AF:

0.00538

AC:

180

AN:

33468

American (AMR)

AF:

0.0227

AC:

1010

AN:

44450

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

820

AN:

26074

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39684

South Asian (SAS)

AF:

0.0144

AC:

1237

AN:

85892

European-Finnish (FIN)

AF:

0.110

AC:

5867

AN:

53304

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0395

AC:

43879

AN:

1110776

Other (OTH)

AF:

0.0351

AC:

2118

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2620

5241

7861

10482

13102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1608

3216

4824

6432

8040

<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:

0.0326

AC:

4958

AN:

152212

Hom.:

157

Cov.:

AF XY:

0.0357

AC XY:

2657

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00722

AC:

300

AN:

41540

American (AMR)

AF:

0.0299

AC:

458

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0118

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.124

AC:

1310

AN:

10576

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0390

AC:

2655

AN:

67998

Other (OTH)

AF:

0.0265

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

242

483

725

966

1208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0340

Hom.:

Bravo

AF:

0.0260

Asia WGS

AF:

0.00606

AC:

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

Jan 20, 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

4.1

(source)

DANN

Benign

0.80

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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