rs41289628

Positions:

chr3-4663132-G-A

Variant summary

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

The NM_001378452.1(ITPR1):c.1480G>A(p.Val494Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,613,778 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 28 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 8.10

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:

ITPR1 (HGNC:):

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=0.009360462).

BP6

Variant 3-4663132-G-A is Benign according to our data. Variant chr3-4663132-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 345684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4663132-G-A is described in Lovd as [Likely_benign]. Variant chr3-4663132-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	15/61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	15/58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	15/61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	15/61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	13/59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 linkuse as main transcript	c.1480G>A	p.Val494Ile	missense_variant	16/59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 linkuse as main transcript	c.1435G>A	p.Val479Ile	missense_variant	15/58	1		ENSP00000397885.2	Q14643-4

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

622

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00620

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00461

AC:

1148

AN:

249094

Hom.:

AF XY:

0.00504

AC XY:

681

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.000711

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00680

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00498

AC:

7280

AN:

1461506

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

3721

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.00961

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00686

Gnomad4 FIN exome

AF:

0.00217

Gnomad4 NFE exome

AF:

0.00525

Gnomad4 OTH exome

AF:

0.00500

GnomAD4 genome

AF:

0.00410

AC:

624

AN:

152272

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

313

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00768

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00620

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00569

Hom.:

Bravo

AF:

0.00386

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00203

AC:

ESP6500EA

AF:

0.00649

AC:

ExAC

AF:

0.00486

AC:

588

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00671

EpiControl

AF:

0.00723

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2019	This variant is associated with the following publications: (PMID: 32859249, 19423733) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ITPR1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 21, 2016	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2024	- -

Autosomal dominant cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

0.095

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;.;.;.;.;D;.;.

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;.

M_CAP

Benign

0.060

MetaRNN

Benign

0.0094

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

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.75

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.89

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

REVEL

Uncertain

0.37

Sift

Benign

0.19

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

Sift4G

Benign

0.21

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

Polyphen

0.0010

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

Vest4

0.19

MVP

0.71

MPC

0.60

ClinPred

0.014

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.36

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