Genetic Variant NM_001036.6:c.12778A>T (chr15-33838758-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001036.6(RYR3):c.12778A>T(p.Ile4260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4260V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

RYR3
NM_001036.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.843

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: G2P, PanelApp Australia, ClinGen
congenital myopathy
Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, PanelApp Australia

RYR3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.081433594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001036.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR3	NM_001036.6	MANE Select	c.12778A>T	p.Ile4260Phe	missense	Exon 89 of 104	NP_001027.3
	RYR3	NM_001243996.4		c.12763A>T	p.Ile4255Phe	missense	Exon 88 of 103	NP_001230925.1	Q15413-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RYR3	ENST00000634891.2	TSL:1 MANE Select	c.12778A>T	p.Ile4260Phe	missense	Exon 89 of 104	ENSP00000489262.1	Q15413-1
RYR3	ENST00000389232.9	TSL:5	c.12775A>T	p.Ile4259Phe	missense	Exon 89 of 104	ENSP00000373884.5	A0A0X1KG73
RYR3	ENST00000415757.7	TSL:2	c.12763A>T	p.Ile4255Phe	missense	Exon 88 of 103	ENSP00000399610.3	Q15413-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

249030

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.98

(source)

DANN

Benign

0.21

DEOGEN2

Uncertain

0.56

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.051

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.2

PhyloP100

0.84

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Benign

0.17

Sift

Benign

0.45

Sift4G

Benign

0.080

Polyphen

0.0040

Vest4

0.25

MutPred

0.48

Loss of helix (P = 0.1706)

MVP

0.17

MPC

0.29

ClinPred

0.029

GERP RS

-3.7

PromoterAI

-0.017

Neutral

(source)

Varity_R

0.058

gMVP

0.24

Mutation Taster

=85/15

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over