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
NM_001378452.1 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 8.10
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 |
---|---|---|---|---|---|---|---|---|
ITPR1 | NM_001378452.1 | c.1480G>A | p.Val494Ile | missense_variant | 16/62 | ENST00000649015.2 | NP_001365381.1 | |
ITPR1 | NM_001168272.2 | c.1435G>A | p.Val479Ile | missense_variant | 15/61 | NP_001161744.1 | ||
ITPR1 | NM_001099952.4 | c.1480G>A | p.Val494Ile | missense_variant | 16/59 | NP_001093422.2 | ||
ITPR1 | NM_002222.7 | c.1435G>A | p.Val479Ile | missense_variant | 15/58 | NP_002213.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ITPR1 | ENST00000649015.2 | c.1480G>A | p.Val494Ile | missense_variant | 16/62 | NM_001378452.1 | ENSP00000497605.1 | |||
ITPR1 | ENST00000354582.12 | c.1480G>A | p.Val494Ile | missense_variant | 16/62 | 5 | ENSP00000346595.8 | |||
ITPR1 | ENST00000648266.1 | c.1480G>A | p.Val494Ile | missense_variant | 16/62 | ENSP00000498014.1 | ||||
ITPR1 | ENST00000650294.1 | c.1435G>A | p.Val479Ile | missense_variant | 15/61 | ENSP00000498056.1 | ||||
ITPR1 | ENST00000443694.5 | c.1435G>A | p.Val479Ile | missense_variant | 15/61 | 1 | ENSP00000401671.2 | |||
ITPR1 | ENST00000648309.1 | c.1435G>A | p.Val479Ile | missense_variant | 13/59 | ENSP00000497026.1 | ||||
ITPR1 | ENST00000357086.10 | c.1480G>A | p.Val494Ile | missense_variant | 16/59 | 1 | ENSP00000349597.4 | |||
ITPR1 | ENST00000456211.8 | c.1435G>A | p.Val479Ile | missense_variant | 15/58 | 1 | ENSP00000397885.2 |
Frequencies
GnomAD3 genomes AF: 0.00409 AC: 622AN: 152154Hom.: 5 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00461 AC: 1148AN: 249094Hom.: 4 AF XY: 0.00504 AC XY: 681AN XY: 135128
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GnomAD4 exome AF: 0.00498 AC: 7280AN: 1461506Hom.: 28 Cov.: 30 AF XY: 0.00512 AC XY: 3721AN XY: 727044
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GnomAD4 genome AF: 0.00410 AC: 624AN: 152272Hom.: 5 Cov.: 32 AF XY: 0.00420 AC XY: 313AN XY: 74466
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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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2019 | This variant is associated with the following publications: (PMID: 32859249, 19423733) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | ITPR1: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 21, 2016 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 12, 2024 | - - |
Autosomal dominant cerebellar ataxia Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;.;D;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.;.;.;.;.;N;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;.;.;.;.;T
Sift4G
Benign
T;T;.;T;.;.;.;.;T
Polyphen
0.0010
.;.;.;.;.;.;B;.;.
Vest4
MVP
MPC
0.60
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at