rs2229633

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR3. . Gene score misZ 4.5522 (greater than the threshold 3.09). Trascript score misZ 5.2589 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease, demyelinating, type 1J.

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 [Likely_benign]. Clinvar id is 774180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33670361-C-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 679 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR3	NM_002224.4 linkuse as main transcript	c.2226C>A	p.Asp742Glu	missense_variant	19/58	ENST00000605930.3	NP_002215.2	Q14573A6H8K3Q59ES2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3 linkuse as main transcript	c.2226C>A	p.Asp742Glu	missense_variant	19/58	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 linkuse as main transcript	c.2226C>A	p.Asp742Glu	missense_variant	20/59	5		ENSP00000363435.4		Q14573

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

GnomAD3 exomes

AF:

0.00299

AC:

751

AN:

250868

Hom.:

AF XY:

0.00294

AC XY:

399

AN XY:

135642

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 SAS exome

AF:

0.00706

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

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.00131

Gnomad4 SAS exome

AF:

0.00679

Gnomad4 FIN exome

AF:

0.00103

Gnomad4 NFE exome

AF:

0.000725

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00446

AC:

679

AN:

152320

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

313

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0114

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00116

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00187

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ITPR3: BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

ITPR3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;D

Eigen

Benign

0.18

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D

MetaRNN

Benign

0.014

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

D;.

REVEL

Uncertain

0.55

Sift

Benign

0.18

T;.

Sift4G

Benign

0.15

T;T

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.28

Gain of relative solvent accessibility (P = 0.1259);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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over