Variant 6-33621627-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_002224.4(ITPR3):c.25C>T(p.His9Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000547 in 1,607,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ITPR3
NM_002224.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

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 Likely_benign. Variant got -5 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=0.15472895).

BS2

High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITPR3	NM_002224.4 linkuse as main transcript	c.25C>T	p.His9Tyr	missense_variant	1/58	ENST00000605930.3
ITPR3	XM_047418731.1 linkuse as main transcript	c.25C>T	p.His9Tyr	missense_variant	2/59
ITPR3	XM_017010832.2 linkuse as main transcript	c.25C>T	p.His9Tyr	missense_variant	2/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR3	ENST00000605930.3 linkuse as main transcript	c.25C>T	p.His9Tyr	missense_variant	1/58	1	NM_002224.4	P1
ITPR3	ENST00000374316.9 linkuse as main transcript	c.25C>T	p.His9Tyr	missense_variant	2/59	5		P1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000627

AC:

AN:

239338

Hom.:

AF XY:

0.0000540

AC XY:

AN XY:

129556

show subpopulations

Gnomad AFR exome

AF:

0.000533

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000928

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1455188

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

723256

show subpopulations

Gnomad4 AFR exome

AF:

0.000659

Gnomad4 AMR exome

AF:

0.0000915

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.000354

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000927

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000660

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.25C>T (p.H9Y) alteration is located in exon 1 (coding exon 1) of the ITPR3 gene. This alteration results from a C to T substitution at nucleotide position 25, causing the histidine (H) at amino acid position 9 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Benign

0.056

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.81

.;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.15

T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.0

D;.

REVEL

Pathogenic

0.66

Sift

Benign

0.12

T;.

Sift4G

Benign

0.080

T;T

Polyphen

0.24

B;B

Vest4

0.43

MVP

0.95

MPC

1.1

ClinPred

0.061

GERP RS

3.7

Varity_R

0.56

gMVP

0.65

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