3-4766606-T-G

Position:

chr3-4766606-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_001378452.1(ITPR1):c.5621T>G(p.Val1874Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,754 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 21 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.59

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 -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.

BP4

Computational evidence support a benign effect (MetaRNN=0.0079301).

BP6

Variant 3-4766606-T-G is Benign according to our data. Variant chr3-4766606-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 289396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ITPR1	NM_001378452.1 linkuse as main transcript	c.5621T>G	p.Val1874Gly	missense_variant	45/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 linkuse as main transcript	c.5576T>G	p.Val1859Gly	missense_variant	44/61		NP_001161744.1
ITPR1	NM_001099952.4 linkuse as main transcript	c.5477T>G	p.Val1826Gly	missense_variant	42/59		NP_001093422.2
ITPR1	NM_002222.7 linkuse as main transcript	c.5432T>G	p.Val1811Gly	missense_variant	41/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.5621T>G	p.Val1874Gly	missense_variant	45/62		NM_001378452.1	ENSP00000497605		Q14643-1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

346

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00829

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00277

AC:

690

AN:

249180

Hom.:

AF XY:

0.00328

AC XY:

443

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00706

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.00327

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00329

AC:

4815

AN:

1461520

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

2509

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00761

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00353

GnomAD4 genome

AF:

0.00229

AC:

348

AN:

152234

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00851

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00337

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00272

Hom.:

Bravo

AF:

0.00197

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00243

AC:

ExAC

AF:

0.00276

AC:

334

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00451

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ITPR1: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2019	- -

ITPR1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

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). -

Autosomal dominant cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.38

.;.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.096

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.47

T;T;T;T;T;T;T;T;.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0079

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.4

.;.;.;.;.;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.62

N;N;.;N;.;.;.;.;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.38

T;T;.;T;.;.;.;.;T;.

Sift4G

Benign

0.36

T;T;.;T;.;.;.;.;T;.

Polyphen

0.078

.;.;.;.;.;.;B;.;.;.

Vest4

0.19

MVP

0.39

MPC

0.20

ClinPred

0.0053

GERP RS

3.3

Varity_R

0.073

gMVP

0.32

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

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