rs797044955

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001378452.1(ITPR1):​c.800C>G​(p.Thr267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T267A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ITPR1
NM_001378452.1 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.82
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-4645672-A-G is described in Lovd as [Pathogenic].
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 3-4645673-C-G is Pathogenic according to our data. Variant chr3-4645673-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ITPR1NM_001378452.1 linkuse as main transcriptc.800C>G p.Thr267Arg missense_variant 10/62 ENST00000649015.2 NP_001365381.1
ITPR1NM_001168272.2 linkuse as main transcriptc.800C>G p.Thr267Arg missense_variant 10/61 NP_001161744.1
ITPR1NM_001099952.4 linkuse as main transcriptc.800C>G p.Thr267Arg missense_variant 10/59 NP_001093422.2
ITPR1NM_002222.7 linkuse as main transcriptc.800C>G p.Thr267Arg missense_variant 10/58 NP_002213.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITPR1ENST00000649015.2 linkuse as main transcriptc.800C>G p.Thr267Arg missense_variant 10/62 NM_001378452.1 ENSP00000497605 Q14643-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsFeb 15, 2018- -
Spinocerebellar ataxia type 29 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.89
.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;.
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Uncertain
2.7
M;M;.;.;M;.;.;.;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-5.6
D;D;.;D;D;.;D;.;.;.;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;.;D;D;.;D;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;.;.;D;.;D;.;.;.;D
Polyphen
1.0, 1.0
.;.;.;.;.;.;D;.;D;.;.
Vest4
0.98
MutPred
0.75
Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);
MVP
0.97
MPC
1.9
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.91
gMVP
0.91

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: rs797044955; hg19: chr3-4687357; API