rs2229633

chr6-33670361-C-Achr6-33670361-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

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 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.13

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ITPR3
• 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]. 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 GnomAd at 679 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR3	NM_002224.4	c.2226C>A	p.Asp742Glu	missense_variant	19/58	ENST00000605930.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR3	ENST00000605930.3	c.2226C>A	p.Asp742Glu	missense_variant	19/58	1	NM_002224.4	P1
ITPR3	ENST00000374316.9	c.2226C>A	p.Asp742Glu	missense_variant	20/59	5		P1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152202 Hom.: 3 Cov.: 32

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.: 1 AF XY: 0.00294 AC XY: 399 AN XY: 135642

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.: 11 Cov.: 32 AF XY: 0.00176 AC XY: 1282 AN XY: 727210

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.: 3 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74484

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.: 0

Bravo AF: 0.00496

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00315 AC: 383

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00207

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

ITPR3-related condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
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	T
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

Other links and lift over

dbSNP: rs2229633; hg19: chr6-33638138;