6-33691695-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002224.4(ITPR3):c.7306C>G(p.Leu2436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 1,613,126 control chromosomes in the GnomAD database, including 209,135 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.47 ( 18127 hom., cov: 30)

Exomes 𝑓: 0.50 ( 191008 hom. )

Consequence

ITPR3
NM_002224.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.687

Publications

49 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.319047E-7).

BP6

Variant 6-33691695-C-G is Benign according to our data. Variant chr6-33691695-C-G is described in ClinVar as Benign. ClinVar VariationId is 1251401.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4 link	c.7306C>G	p.Leu2436Val	missense_variant	Exon 53 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.7306C>G	p.Leu2436Val	missense_variant	Exon 53 of 58	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 link	c.7306C>G	p.Leu2436Val	missense_variant	Exon 54 of 59	5		ENSP00000363435.4		Q14573

Frequencies

GnomAD3 genomes

AF:

0.467

AC:

70811

AN:

151716

Hom.:

18107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.299

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.484

Gnomad EAS

AF:

0.901

Gnomad SAS

AF:

0.806

Gnomad FIN

AF:

0.625

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.447

GnomAD2 exomes

AF:

0.572

AC:

143588

AN:

251116

AF XY:

0.582

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.655

Gnomad ASJ exome

AF:

0.471

Gnomad EAS exome

AF:

0.918

Gnomad FIN exome

AF:

0.615

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.498

AC:

727342

AN:

1461292

Hom.:

191008

Cov.:

AF XY:

0.508

AC XY:

369063

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.290

AC:

9719

AN:

33466

American (AMR)

AF:

0.640

AC:

28634

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.476

AC:

12438

AN:

26132

East Asian (EAS)

AF:

0.865

AC:

34351

AN:

39700

South Asian (SAS)

AF:

0.781

AC:

67399

AN:

86252

European-Finnish (FIN)

AF:

0.609

AC:

32532

AN:

53396

Middle Eastern (MID)

AF:

0.475

AC:

2738

AN:

5766

European-Non Finnish (NFE)

AF:

0.458

AC:

509256

AN:

1111490

Other (OTH)

AF:

0.501

AC:

30275

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

18611

37222

55834

74445

93056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15316

30632

45948

61264

76580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.467

AC:

70861

AN:

151834

Hom.:

18127

Cov.:

AF XY:

0.486

AC XY:

36039

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.299

AC:

12355

AN:

41386

American (AMR)

AF:

0.550

AC:

8409

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

1679

AN:

3472

East Asian (EAS)

AF:

0.901

AC:

4632

AN:

5140

South Asian (SAS)

AF:

0.807

AC:

3870

AN:

4798

European-Finnish (FIN)

AF:

0.625

AC:

6582

AN:

10536

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.468

AC:

31777

AN:

67906

Other (OTH)

AF:

0.453

AC:

955

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1748

3497

5245

6994

8742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.471

Hom.:

5581

Bravo

AF:

0.449

TwinsUK

AF:

0.447

AC:

1656

ALSPAC

AF:

0.463

AC:

1785

ESP6500AA

AF:

0.308

AC:

1356

ESP6500EA

AF:

0.460

AC:

3956

ExAC

AF:

0.567

AC:

68894

Asia WGS

AF:

0.786

AC:

2732

AN:

3478

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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

1.7

(source)

DANN

Benign

0.21

DEOGEN2

Uncertain

0.51

D;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0056

LIST_S2

Benign

0.041

.;T

MetaRNN

Benign

8.3e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

L;L

PhyloP100

0.69

PrimateAI

Benign

0.40

PROVEAN

Benign

1.0

N;.

REVEL

Benign

0.076

Sift

Benign

0.76

T;.

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.043

MPC

0.70

ClinPred

0.0059

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.059

gMVP

0.20

Mutation Taster

=100/0

polymorphism (auto)

(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

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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