rs200335594

Positions:

chr3-4670726-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001378452.1(ITPR1):c.2007-3T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005515

Clinical Significance

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

Conservation

PhyloP100: 0.343

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 194942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4670726-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ITPR1	NM_001378452.1 linkuse as main transcript	c.2007-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001099952.4 linkuse as main transcript	c.2007-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001093422.2
ITPR1	NM_001168272.2 linkuse as main transcript	c.1962-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001161744.1
ITPR1	NM_002222.7 linkuse as main transcript	c.1962-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.2007-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001378452.1	ENSP00000497605		Q14643-1

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

GnomAD3 exomes

AF:

0.00100

AC:

198

AN:

198044

Hom.:

AF XY:

0.00107

AC XY:

113

AN XY:

105702

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 SAS 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

Gnomad4 AFR exome

AF:

0.000368

Gnomad4 AMR exome

AF:

0.000414

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.00282

Gnomad4 OTH exome

AF:

0.00110

GnomAD4 genome

AF:

0.00142

AC:

216

AN:

152358

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00262

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00167

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	ITPR1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 11, 2021	- -

See cases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 14, 2020

ACMG classification criteria: BS1, BP4 -

ITPR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2022

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.0

DANN

Benign

0.63

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

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