6-33621627-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease, demyelinating, type 1J
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ITPR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

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 rank	MANE	Protein	UniProt
ITPR3	NM_002224.4 link	c.25C>T	p.His9Tyr	missense_variant	Exon 1 of 58	ENST00000605930.3	NP_002215.2	Q14573A6H8K3Q59ES2
ITPR3	XM_047418731.1 link	c.25C>T	p.His9Tyr	missense_variant	Exon 2 of 59		XP_047274687.1
ITPR3	XM_017010832.2 link	c.25C>T	p.His9Tyr	missense_variant	Exon 2 of 32		XP_016866321.1
ITPR3	XM_047418732.1 link	c.-336C>T		upstream_gene_variant			XP_047274688.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3 link	c.25C>T	p.His9Tyr	missense_variant	Exon 1 of 58	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 link	c.25C>T	p.His9Tyr	missense_variant	Exon 2 of 59	5		ENSP00000363435.4		Q14573

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

GnomAD2 exomes

AF:

0.0000627

AC:

AN:

239338

AF XY:

0.0000540

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 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

African (AFR)

AF:

0.000659

AC:

AN:

33408

American (AMR)

AF:

0.0000915

AC:

AN:

43692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.00

AC:

AN:

85096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52774

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108868

Other (OTH)

AF:

0.0000998

AC:

AN:

60126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000354

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41596

American (AMR)

AF:

0.000457

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000147

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

Jan 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

4.2

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

PromoterAI

-0.035

Neutral

(source)

Varity_R

0.56

gMVP

0.65

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-33621627-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over