rs1553689752

Positions:

• chr3-4680564-T-TTATA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: 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	Protein	UniProt
ITPR1	NM_001378452.1	c.2979_2980insTATA	p.Val994TyrfsTer7	frameshift_variant	25/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001099952.4	c.2952_2953insTATA	p.Val985TyrfsTer7	frameshift_variant	25/59		NP_001093422.2
ITPR1	NM_001168272.2	c.2934_2935insTATA	p.Val979TyrfsTer7	frameshift_variant	24/61		NP_001161744.1
ITPR1	NM_002222.7	c.2907_2908insTATA	p.Val970TyrfsTer7	frameshift_variant	24/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2979_2980insTATA	p.Val994TyrfsTer7	frameshift_variant	25/62		NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gillespie syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553689752; hg19: chr3-4722248;