rs746724784
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001378452.1(ITPR1):c.6808+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,202 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
ITPR1
NM_001378452.1 splice_donor_region, intron
NM_001378452.1 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0007844
2
Clinical Significance
Conservation
PhyloP100: 1.44
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 Likely_benign. Variant got -4 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.66).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITPR1 | NM_001378452.1 | c.6808+4G>A | splice_donor_region_variant, intron_variant | ENST00000649015.2 | |||
ITPR1 | NM_001099952.4 | c.6664+4G>A | splice_donor_region_variant, intron_variant | ||||
ITPR1 | NM_001168272.2 | c.6763+4G>A | splice_donor_region_variant, intron_variant | ||||
ITPR1 | NM_002222.7 | c.6619+4G>A | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITPR1 | ENST00000649015.2 | c.6808+4G>A | splice_donor_region_variant, intron_variant | NM_001378452.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000922 AC: 2AN: 216864Hom.: 0 AF XY: 0.0000172 AC XY: 2AN XY: 116108
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GnomAD4 exome AF: 0.0000104 AC: 15AN: 1442016Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 8AN XY: 715128
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 02, 2019 | 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 586053). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change falls in intron 48 of the ITPR1 gene. It does not directly change the encoded amino acid sequence of the ITPR1 protein, but it affects a nucleotide within the consensus splice site of the intron. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 29, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at