rs3749383

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378452.1(ITPR1):c.4288A>G(p.Ile1430Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,610,434 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 44 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.42

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 -19 ACMG points.

PP2

Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076238215).

BP6

Variant 3-4697153-A-G is Benign according to our data. Variant chr3-4697153-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 345737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00137 (209/152300) while in subpopulation EAS AF= 0.0359 (186/5176). AF 95% confidence interval is 0.0317. There are 6 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.4288A>G	p.Ile1430Val	missense_variant	Exon 34 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.4243A>G	p.Ile1415Val	missense_variant	Exon 33 of 61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.4261A>G	p.Ile1421Val	missense_variant	Exon 34 of 59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.4216A>G	p.Ile1406Val	missense_variant	Exon 33 of 58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.4288A>G	p.Ile1430Val	missense_variant	Exon 34 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.4261A>G	p.Ile1421Val	missense_variant	Exon 34 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.4261A>G	p.Ile1421Val	missense_variant	Exon 34 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.4243A>G	p.Ile1415Val	missense_variant	Exon 33 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.4243A>G	p.Ile1415Val	missense_variant	Exon 33 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.4216A>G	p.Ile1406Val	missense_variant	Exon 31 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.4261A>G	p.Ile1421Val	missense_variant	Exon 34 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.4216A>G	p.Ile1406Val	missense_variant	Exon 33 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.2098A>G	p.Ile700Val	missense_variant	Exon 15 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.1588A>G	p.Ile530Val	missense_variant	Exon 12 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.1195A>G	p.Ile399Val	missense_variant	Exon 10 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0359

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00287

AC:

699

AN:

243204

Hom.:

AF XY:

0.00276

AC XY:

364

AN XY:

131736

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0377

Gnomad SAS exome

AF:

0.000474

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00119

AC:

1741

AN:

1458134

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

844

AN XY:

724910

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0368

Gnomad4 SAS exome

AF:

0.000820

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.00275

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152300

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0359

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.00161

ESP6500AA

AF:

0.000531

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00291

AC:

351

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Oct 15, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29

Benign:1

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia

Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

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

Eigen

Benign

0.0011

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

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

MetaRNN

Benign

0.0076

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

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

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.15

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

REVEL

Benign

0.14

Sift

Benign

0.30

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

Sift4G

Benign

0.28

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

Polyphen

0.059

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

Vest4

0.28

MVP

0.21

MPC

0.64

ClinPred

0.033

GERP RS

5.1

Varity_R

0.097

gMVP

0.13

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