rs753499808

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001378452.1(ITPR1):​c.7042A>G​(p.Thr2348Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.88
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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=0.3210718).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITPR1NM_001378452.1 linkc.7042A>G p.Thr2348Ala missense_variant Exon 54 of 62 ENST00000649015.2 NP_001365381.1
ITPR1NM_001168272.2 linkc.6997A>G p.Thr2333Ala missense_variant Exon 53 of 61 NP_001161744.1 Q14643-2
ITPR1NM_001099952.4 linkc.6898A>G p.Thr2300Ala missense_variant Exon 51 of 59 NP_001093422.2 Q14643-3B4DER3Q59H91
ITPR1NM_002222.7 linkc.6853A>G p.Thr2285Ala missense_variant Exon 50 of 58 NP_002213.5 Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITPR1ENST00000649015.2 linkc.7042A>G p.Thr2348Ala missense_variant Exon 54 of 62 NM_001378452.1 ENSP00000497605.1 Q14643-1
ITPR1ENST00000354582.12 linkc.7018A>G p.Thr2340Ala missense_variant Exon 54 of 62 5 ENSP00000346595.8 A0A3F2YNW8
ITPR1ENST00000648266.1 linkc.7015A>G p.Thr2339Ala missense_variant Exon 54 of 62 ENSP00000498014.1 A0A3B3IU04
ITPR1ENST00000650294.1 linkc.7000A>G p.Thr2334Ala missense_variant Exon 53 of 61 ENSP00000498056.1 A0A3B3ITU8
ITPR1ENST00000443694.5 linkc.6997A>G p.Thr2333Ala missense_variant Exon 53 of 61 1 ENSP00000401671.2 Q14643-2
ITPR1ENST00000648309.1 linkc.6970A>G p.Thr2324Ala missense_variant Exon 51 of 59 ENSP00000497026.1 Q14643-5
ITPR1ENST00000357086.10 linkc.6898A>G p.Thr2300Ala missense_variant Exon 51 of 59 1 ENSP00000349597.4 Q14643-3
ITPR1ENST00000456211.8 linkc.6853A>G p.Thr2285Ala missense_variant Exon 50 of 58 1 ENSP00000397885.2 Q14643-4
ITPR1ENST00000648038.1 linkc.4804A>G p.Thr1602Ala missense_variant Exon 34 of 42 ENSP00000497872.1 A0A3B3ITQ1
ITPR1ENST00000648431.1 linkc.4219A>G p.Thr1407Ala missense_variant Exon 31 of 39 ENSP00000498149.1 A0A3B3IU05
ITPR1ENST00000648212.1 linkc.3982A>G p.Thr1328Ala missense_variant Exon 31 of 39 ENSP00000498022.1 A0A3B3IU13

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249270
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135240
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461706
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jun 05, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 586054). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITPR1 protein function. This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is present in population databases (rs753499808, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2285 of the ITPR1 protein (p.Thr2285Ala). -

Jan 20, 2021
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
.;.;.;.;.;.;D;.;.;.
Eigen
Benign
0.033
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;.;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.044
D
MutationAssessor
Benign
1.7
.;.;.;.;.;.;L;.;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.8
D;D;.;D;.;.;.;.;D;.
REVEL
Uncertain
0.47
Sift
Benign
0.52
T;T;.;T;.;.;.;.;T;.
Sift4G
Benign
0.28
T;T;.;T;.;.;.;.;T;.
Polyphen
0.013
.;.;.;.;.;.;B;.;.;.
Vest4
0.46
MutPred
0.34
.;.;.;.;.;.;Gain of methylation at R2351 (P = 0.0904);.;.;.;
MVP
0.85
MPC
0.87
ClinPred
0.49
T
GERP RS
5.1
Varity_R
0.20
gMVP
0.80

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.

Other links and lift over

dbSNP: rs753499808; hg19: chr3-4842219; API