Genetic Variant ITPR3:p.Gly756Gly (chr6-33670403-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002224.4(ITPR3):c.2268C>T(p.Gly756Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,780 control chromosomes in the GnomAD database, including 86,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.28 ( 6340 hom., cov: 32)

Exomes 𝑓: 0.32 ( 79707 hom. )

Consequence

ITPR3
NM_002224.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -3.15

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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 6-33670403-C-T is Benign according to our data. Variant chr6-33670403-C-T is described in ClinVar as [Benign]. Clinvar id is 1293559.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-3.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4 link	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 19 of 58	ENST00000605930.3	NP_002215.2	Q14573A6H8K3Q59ES2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3 link	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 19 of 58	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 link	c.2268C>T	p.Gly756Gly	synonymous_variant	Exon 20 of 59	5		ENSP00000363435.4		Q14573

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

42000

AN:

151924

Hom.:

6331

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.347

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.512

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.300

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.327

AC:

82161

AN:

251298

Hom.:

14637

AF XY:

0.340

AC XY:

46179

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.185

Gnomad EAS exome

AF:

0.477

Gnomad SAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.360

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.323

AC:

471951

AN:

1461738

Hom.:

79707

Cov.:

AF XY:

0.329

AC XY:

238983

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.176

Gnomad4 AMR exome

AF:

0.259

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.465

Gnomad4 SAS exome

AF:

0.506

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.312

Gnomad4 OTH exome

AF:

0.320

GnomAD4 genome

AF:

0.276

AC:

42030

AN:

152042

Hom.:

6340

Cov.:

AF XY:

0.283

AC XY:

21055

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.478

Gnomad4 SAS

AF:

0.512

Gnomad4 FIN

AF:

0.362

Gnomad4 NFE

AF:

0.300

Gnomad4 OTH

AF:

0.272

Alfa

AF:

0.299

Hom.:

17357

Bravo

AF:

0.260

Asia WGS

AF:

0.510

AC:

1770

AN:

3478

EpiCase

AF:

0.296

EpiControl

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ITPR3-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

5.5

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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