rs1553654413

Variant names:

• chr3-4627876-CACGT-C
• rs1553654413
• NM_001378452.1:c.279+4_279+7delCGTA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001378452.1(ITPR1):​c.279+4_279+7delCGTA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92
• Publications: 1 publications found

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]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-4627876-CACGT-C is Pathogenic according to our data. Variant chr3-4627876-CACGT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 437908.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.279+4_279+7delCGTA		splice_region_variant, intron_variant	Intron 5 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.279+4_279+7delCGTA		splice_region_variant, intron_variant	Intron 5 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.279+4_279+7delCGTA		splice_region_variant, intron_variant	Intron 5 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.279+4_279+7delCGTA		splice_region_variant, intron_variant	Intron 5 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 3 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.278_279+2delACGT	p.His93ProfsTer21	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 5 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gillespie syndrome Pathogenic:1

Nov 14, 2016

Laboratory of Molecular Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The deletion, mapping in the 5' region of ITPR1 gene, abolished the splice-donor site at exon 5/intron 5 junction, causing the skipping of the exon 5 and resulting in generation of a premature STOP codon, with production of a 64-amino acids non-functional protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 2

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

Other links and lift over

dbSNP: rs1553654413; hg19: chr3-4669560;