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GeneBe

rs1553689752

chr3-4680564-T-TTATA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001378452.1(ITPR1):c.2979_2980insTATA(p.Val994TyrfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. N993N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

ITPR1
NM_001378452.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.51
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 12 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-4680564-T-TTATA is Pathogenic according to our data. Variant chr3-4680564-T-TTATA is described in ClinVar as [Pathogenic]. Clinvar id is 438828.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ITPR1NM_001378452.1 linkuse as main transcriptc.2979_2980insTATA p.Val994TyrfsTer7 frameshift_variant 25/62 ENST00000649015.2
ITPR1NM_001099952.4 linkuse as main transcriptc.2952_2953insTATA p.Val985TyrfsTer7 frameshift_variant 25/59
ITPR1NM_001168272.2 linkuse as main transcriptc.2934_2935insTATA p.Val979TyrfsTer7 frameshift_variant 24/61
ITPR1NM_002222.7 linkuse as main transcriptc.2907_2908insTATA p.Val970TyrfsTer7 frameshift_variant 24/58

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ITPR1ENST00000649015.2 linkuse as main transcriptc.2979_2980insTATA p.Val994TyrfsTer7 frameshift_variant 25/62 NM_001378452.1 Q14643-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Gillespie syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs1553689752; hg19: chr3-4722248; API