rs2229633

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002224.4(ITPR3):c.2226C>A(p.Asp742Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,118 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D742D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 11 hom. )

Consequence

ITPR3
NM_002224.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.13

Publications

11 publications found

Variant links:

Genes affected

ITPR3 (HGNC:6182): (inositol 1,4,5-trisphosphate receptor type 3) This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]

ITPR3 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease, demyelinating, type 1J
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ITPR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0137833655).

BP6

Variant 6-33670361-C-A is Benign according to our data. Variant chr6-33670361-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 774180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 679 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002224.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	NM_002224.4	MANE Select	c.2226C>A	p.Asp742Glu	missense	Exon 19 of 58	NP_002215.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.2226C>A	p.Asp742Glu	missense	Exon 19 of 58	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.2226C>A	p.Asp742Glu	missense	Exon 20 of 59	ENSP00000363435.4

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

679

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00299

AC:

751

AN:

250868

AF XY:

0.00294

show subpopulations

Gnomad AFR exome

AF:

0.0129

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.000880

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00159

AC:

2323

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

1282

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0110

AC:

368

AN:

33480

American (AMR)

AF:

0.00282

AC:

126

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00612

AC:

160

AN:

26136

East Asian (EAS)

AF:

0.00131

AC:

AN:

39700

South Asian (SAS)

AF:

0.00679

AC:

586

AN:

86258

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000725

AC:

806

AN:

1112010

Other (OTH)

AF:

0.00194

AC:

117

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

157

314

471

628

785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00446

AC:

679

AN:

152320

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

313

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0114

AC:

475

AN:

41566

American (AMR)

AF:

0.00307

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00213

AC:

AN:

5174

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00267

Hom.:

Bravo

AF:

0.00496

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00315

AC:

383

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

ITPR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Benign

0.18

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.3

PhyloP100

2.1

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.55

Sift

Benign

0.18

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.63

MutPred

0.28

Gain of relative solvent accessibility (P = 0.1259)

MVP

0.93

MPC

1.2

ClinPred

0.024

GERP RS

2.9

Varity_R

0.49

gMVP

0.64

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over