3-4779607-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BS1_Supporting

The NM_001378452.1(ITPR1):c.6349G>T(p.Ala2117Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000726 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 9.91

Publications

6 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:

ENSG00000235978 (HGNC:):

ENSG00000235978 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001378452.1

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000855 (13/152122) while in subpopulation NFE AF = 0.000191 (13/68024). AF 95% confidence interval is 0.000112. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.6349G>T	p.Ala2117Ser	missense_variant	Exon 49 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.6304G>T	p.Ala2102Ser	missense_variant	Exon 48 of 61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.6205G>T	p.Ala2069Ser	missense_variant	Exon 46 of 59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.6160G>T	p.Ala2054Ser	missense_variant	Exon 45 of 58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.6349G>T	p.Ala2117Ser	missense_variant	Exon 49 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.6325G>T	p.Ala2109Ser	missense_variant	Exon 49 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.6322G>T	p.Ala2108Ser	missense_variant	Exon 49 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.6307G>T	p.Ala2103Ser	missense_variant	Exon 48 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.6304G>T	p.Ala2102Ser	missense_variant	Exon 48 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.6277G>T	p.Ala2093Ser	missense_variant	Exon 46 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.6205G>T	p.Ala2069Ser	missense_variant	Exon 46 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.6160G>T	p.Ala2054Ser	missense_variant	Exon 45 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.4111G>T	p.Ala1371Ser	missense_variant	Exon 29 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.3649G>T	p.Ala1217Ser	missense_variant	Exon 27 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.3256G>T	p.Ala1086Ser	missense_variant	Exon 25 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000562

AC:

AN:

249160

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000712

AC:

104

AN:

1459922

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

726322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.0000224

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

1110660

Other (OTH)

AF:

0.0000498

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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:

0.000225

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ITPR1: PP2, PP3 -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2054 of the ITPR1 protein (p.Ala2054Ser). This variant is present in population databases (rs373973399, gnomAD 0.02%). This missense change has been observed in individual(s) with clincial features of hereditary spastic paraplegia (PMID: 30778698). This variant is also known as c.6304G>T (p.Ala2102Ser). ClinVar contains an entry for this variant (Variation ID: 503524). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ITPR1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 13, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in a cohort of patients with a diagnosis of large-vessel ischemic stroke; however, segregation information was not provided (Janicki et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30778698, 29232918) -

ITPR1-related disorder

Uncertain:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ITPR1 c.6160G>T variant is predicted to result in the amino acid substitution p.Ala2054Ser. This variant has been reported along with second ITPR1 variant in an individual with spastic paraplegia (reported as c.6304G>T (p.Ala2102Ser), Elert-Dobkowska et al. 2019. PubMed ID: 30778698). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant cerebellar ataxia

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Spinocerebellar ataxia type 29

Benign:1

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.58

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

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.7

.;.;.;.;.;.;M;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.61

Sift

Benign

0.052

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

Sift4G

Benign

0.078

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

Polyphen

0.56

.;.;.;.;.;.;P;.;.;.

Vest4

0.81

MVP

0.74

MPC

0.89

ClinPred

0.38

GERP RS

4.4

Varity_R

0.40

gMVP

0.74

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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