rs41289628

Positions:

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

1
8
10

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]

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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
ITPR1NM_001378452.1 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/62 ENST00000649015.2 NP_001365381.1
ITPR1NM_001168272.2 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 15/61 NP_001161744.1 Q14643-2
ITPR1NM_001099952.4 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/59 NP_001093422.2 Q14643-3B4DER3Q59H91
ITPR1NM_002222.7 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 15/58 NP_002213.5 Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITPR1ENST00000649015.2 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/62 NM_001378452.1 ENSP00000497605.1 Q14643-1
ITPR1ENST00000354582.12 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/625 ENSP00000346595.8 A0A3F2YNW8
ITPR1ENST00000648266.1 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/62 ENSP00000498014.1 A0A3B3IU04
ITPR1ENST00000650294.1 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 15/61 ENSP00000498056.1 A0A3B3ITU8
ITPR1ENST00000443694.5 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 15/611 ENSP00000401671.2 Q14643-2
ITPR1ENST00000648309.1 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 13/59 ENSP00000497026.1 Q14643-5
ITPR1ENST00000357086.10 linkuse as main transcriptc.1480G>A p.Val494Ile missense_variant 16/591 ENSP00000349597.4 Q14643-3
ITPR1ENST00000456211.8 linkuse as main transcriptc.1435G>A p.Val479Ile missense_variant 15/581 ENSP00000397885.2 Q14643-4

Frequencies

GnomAD3 genomes
AF:
0.00409
AC:
622
AN:
152154
Hom.:
5
Cov.:
32
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.:
4
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.:
28
Cov.:
30
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.:
5
Cov.:
32
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.:
9
Bravo
AF:
0.00386
TwinsUK
AF:
0.00405
AC:
15
ALSPAC
AF:
0.00571
AC:
22
ESP6500AA
AF:
0.00203
AC:
8
ESP6500EA
AF:
0.00649
AC:
54
ExAC
AF:
0.00486
AC:
588
Asia WGS
AF:
0.00404
AC:
14
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 27, 2019This variant is associated with the following publications: (PMID: 32859249, 19423733) -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2024ITPR1: BS2 -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 21, 2016- -
not specified Benign:2
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 12, 2024- -
Autosomal dominant cerebellar ataxia Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
.;.;.;.;.;.;D;.;.
Eigen
Benign
0.11
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D;.
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.0094
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
0.75
N;.;.;.;.;.;N;.;.
PrimateAI
Uncertain
0.63
T
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
T
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.

Other links and lift over

dbSNP: rs41289628; hg19: chr3-4704816; COSMIC: COSV56991440; API