3-4814496-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378452.1(ITPR1):c.7635T>C(p.Thr2545Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,613,016 control chromosomes in the GnomAD database, including 554,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49235 hom., cov: 29)

Exomes 𝑓: 0.83 ( 504868 hom. )

Consequence

ITPR1
NM_001378452.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.33

Publications

24 publications found

Variant links:

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

ENSG00000235978 (HGNC:):

ENSG00000235978 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 3-4814496-T-C is Benign according to our data. Variant chr3-4814496-T-C is described in ClinVar as Benign. ClinVar VariationId is 129303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.7635T>C	p.Thr2545Thr	synonymous_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.7635T>C	p.Thr2545Thr	synonymous_variant	Exon 58 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.7611T>C	p.Thr2537Thr	synonymous_variant	Exon 58 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.7608T>C	p.Thr2536Thr	synonymous_variant	Exon 58 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.7593T>C	p.Thr2531Thr	synonymous_variant	Exon 57 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.7590T>C	p.Thr2530Thr	synonymous_variant	Exon 57 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.7563T>C	p.Thr2521Thr	synonymous_variant	Exon 55 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.7491T>C	p.Thr2497Thr	synonymous_variant	Exon 55 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.7446T>C	p.Thr2482Thr	synonymous_variant	Exon 54 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.5397T>C	p.Thr1799Thr	synonymous_variant	Exon 38 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.4812T>C	p.Thr1604Thr	synonymous_variant	Exon 35 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.4575T>C	p.Thr1525Thr	synonymous_variant	Exon 35 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.802

AC:

121641

AN:

151684

Hom.:

49209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.707

Gnomad AMI

AF:

0.881

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.803

Gnomad EAS

AF:

0.962

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.833

Gnomad OTH

AF:

0.773

GnomAD2 exomes

AF:

0.829

AC:

206711

AN:

249264

AF XY:

0.824

show subpopulations

Gnomad AFR exome

AF:

0.696

Gnomad AMR exome

AF:

0.843

Gnomad ASJ exome

AF:

0.807

Gnomad EAS exome

AF:

0.968

Gnomad FIN exome

AF:

0.912

Gnomad NFE exome

AF:

0.833

Gnomad OTH exome

AF:

0.816

GnomAD4 exome

AF:

0.830

AC:

1212796

AN:

1461214

Hom.:

504868

Cov.:

AF XY:

0.827

AC XY:

601450

AN XY:

726908

show subpopulations

African (AFR)

AF:

0.697

AC:

23346

AN:

33472

American (AMR)

AF:

0.838

AC:

37464

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.808

AC:

21106

AN:

26132

East Asian (EAS)

AF:

0.936

AC:

37162

AN:

39694

South Asian (SAS)

AF:

0.745

AC:

64261

AN:

86238

European-Finnish (FIN)

AF:

0.909

AC:

48523

AN:

53394

Middle Eastern (MID)

AF:

0.739

AC:

4256

AN:

5762

European-Non Finnish (NFE)

AF:

0.834

AC:

927270

AN:

1111448

Other (OTH)

AF:

0.819

AC:

49408

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

10159

20318

30476

40635

50794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21046

42092

63138

84184

105230

<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:

0.802

AC:

121715

AN:

151802

Hom.:

49235

Cov.:

AF XY:

0.805

AC XY:

59730

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.708

AC:

29246

AN:

41328

American (AMR)

AF:

0.802

AC:

12243

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.803

AC:

2780

AN:

3464

East Asian (EAS)

AF:

0.962

AC:

4929

AN:

5124

South Asian (SAS)

AF:

0.736

AC:

3543

AN:

4812

European-Finnish (FIN)

AF:

0.923

AC:

9743

AN:

10552

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.833

AC:

56625

AN:

67954

Other (OTH)

AF:

0.765

AC:

1612

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1144

2288

3433

4577

5721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

872

1744

2616

3488

4360

<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:

0.817

Hom.:

99953

Bravo

AF:

0.795

Asia WGS

AF:

0.802

AC:

2790

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:4

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Gillespie syndrome

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia type 29

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant cerebellar ataxia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinocerebellar ataxia type 15/16

Benign:1

Aug 19, 2021

Genome-Nilou Lab

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

-0.78

CADD

Benign

0.49

(source)

DANN

Benign

0.67

PhyloP100

-1.3

PromoterAI

-0.072

Neutral

(source)

Mutation Taster

=97/3

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