chr3-4670726-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378452.1(ITPR1):c.2007-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,570,614 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 9 hom. )

Consequence

ITPR1
NM_001378452.1 splice_region, intron

Scores

Splicing: ADA: 0.00005515

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.343

Publications

1 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:

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=-0.85).

BP6

Variant 3-4670726-T-C is Benign according to our data. Variant chr3-4670726-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (216/152358) while in subpopulation NFE AF = 0.00262 (178/68028). AF 95% confidence interval is 0.0023. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ITPR1	NM_001378452.1 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 18 of 60		NP_001161744.1
ITPR1	NM_001099952.4 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 58		NP_001093422.2
ITPR1	NM_002222.7 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 18 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ITPR1	ENST00000649015.2 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 18 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 18 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 16 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10 link	c.2007-3T>C	splice_region_variant, intron_variant	Intron 19 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8 link	c.1962-3T>C	splice_region_variant, intron_variant	Intron 18 of 57	1		ENSP00000397885.2
ITPR1	ENST00000648038.1 link	c.-160T>C	upstream_gene_variant				ENSP00000497872.1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00262

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00100

AC:

198

AN:

198044

AF XY:

0.00107

show subpopulations

Gnomad AFR exome

AF:

0.000338

Gnomad AMR exome

AF:

0.000356

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000209

Gnomad NFE exome

AF:

0.00206

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00224

AC:

3183

AN:

1418256

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1494

AN XY:

702570

show subpopulations

African (AFR)

AF:

0.000368

AC:

AN:

32600

American (AMR)

AF:

0.000414

AC:

AN:

38630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25486

East Asian (EAS)

AF:

0.00

AC:

AN:

38542

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81326

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

51550

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00282

AC:

3061

AN:

1085480

Other (OTH)

AF:

0.00110

AC:

AN:

58992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

130

261

391

522

652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00142

AC:

216

AN:

152358

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41584

American (AMR)

AF:

0.000784

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00262

AC:

178

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00160

Hom.:

Bravo

AF:

0.00147

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 02, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITPR1: BP4 -

not specified

Benign:2

Feb 26, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Benign:1

Feb 14, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: BS1, BP4 -

ITPR1-related disorder

Benign:1

Jun 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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. -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.0

(source)

DANN

Benign

0.63

PhyloP100

0.34

PromoterAI

-0.0026

Neutral

(source)

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.034

SpliceAI score (max)

0.010

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