rs12528378

Positions:

chr6-33685709-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBA1

The NM_002224.4(ITPR3):c.5549G>A(p.Arg1850Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 1,606,212 control chromosomes in the GnomAD database, including 6,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.062 ( 423 hom., cov: 33)

Exomes 𝑓: 0.084 ( 5656 hom. )

Consequence

ITPR3
NM_002224.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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=0.0015537739).

BP6

Variant 6-33685709-G-A is Benign according to our data. Variant chr6-33685709-G-A is described in ClinVar as [Benign]. Clinvar id is 1293577.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR3	NM_002224.4 linkuse as main transcript	c.5549G>A	p.Arg1850Gln	missense_variant	41/58	ENST00000605930.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR3	ENST00000605930.3 linkuse as main transcript	c.5549G>A	p.Arg1850Gln	missense_variant	41/58	1	NM_002224.4	P1
ITPR3	ENST00000374316.9 linkuse as main transcript	c.5549G>A	p.Arg1850Gln	missense_variant	42/59	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0624

AC:

9495

AN:

152198

Hom.:

423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.0514

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.00539

Gnomad SAS

AF:

0.0255

Gnomad FIN

AF:

0.0719

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0988

Gnomad OTH

AF:

0.0659

GnomAD3 exomes

AF:

0.0631

AC:

15491

AN:

245564

Hom.:

655

AF XY:

0.0632

AC XY:

8400

AN XY:

132960

show subpopulations

Gnomad AFR exome

AF:

0.0150

Gnomad AMR exome

AF:

0.0401

Gnomad ASJ exome

AF:

0.0403

Gnomad EAS exome

AF:

0.00516

Gnomad SAS exome

AF:

0.0279

Gnomad FIN exome

AF:

0.0732

Gnomad NFE exome

AF:

0.0961

Gnomad OTH exome

AF:

0.0682

GnomAD4 exome

AF:

0.0838

AC:

121858

AN:

1453896

Hom.:

5656

Cov.:

AF XY:

0.0821

AC XY:

59306

AN XY:

722086

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.0434

Gnomad4 ASJ exome

AF:

0.0417

Gnomad4 EAS exome

AF:

0.00382

Gnomad4 SAS exome

AF:

0.0277

Gnomad4 FIN exome

AF:

0.0724

Gnomad4 NFE exome

AF:

0.0969

Gnomad4 OTH exome

AF:

0.0742

GnomAD4 genome

AF:

0.0623

AC:

9493

AN:

152316

Hom.:

423

Cov.:

AF XY:

0.0612

AC XY:

4555

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0160

Gnomad4 AMR

AF:

0.0514

Gnomad4 ASJ

AF:

0.0415

Gnomad4 EAS

AF:

0.00541

Gnomad4 SAS

AF:

0.0253

Gnomad4 FIN

AF:

0.0719

Gnomad4 NFE

AF:

0.0988

Gnomad4 OTH

AF:

0.0652

Alfa

AF:

0.0860

Hom.:

945

Bravo

AF:

0.0591

TwinsUK

AF:

0.0979

AC:

363

ALSPAC

AF:

0.0781

AC:

301

ESP6500AA

AF:

0.0197

AC:

ESP6500EA

AF:

0.0993

AC:

854

ExAC

AF:

0.0638

AC:

7740

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ITPR3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2020

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.80

.;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.61

N;.

REVEL

Benign

0.19

Sift

Benign

0.49

T;.

Sift4G

Benign

0.62

T;T

Polyphen

0.30

B;B

Vest4

0.072

MPC

0.47

ClinPred

0.0040

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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