chr3-4627876-CACGT-C

Position:

• chr3-4627876-CACGT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001378452.1(ITPR1):​c.279+4_279+7del variant causes a splice donor, coding sequence 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_donor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of 31, new splice context is: gtaGTgagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4627876-CACGT-C is Pathogenic according to our data. Variant chr3-4627876-CACGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 437908.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.279+4_279+7del		splice_donor_variant, coding_sequence_variant	5/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001099952.4	c.279+4_279+7del		splice_donor_variant, coding_sequence_variant	5/59		NP_001093422.2
ITPR1	NM_001168272.2	c.279+4_279+7del		splice_donor_variant, coding_sequence_variant	5/61		NP_001161744.1
ITPR1	NM_002222.7	c.279+4_279+7del		splice_donor_variant, coding_sequence_variant	5/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.279+4_279+7del		splice_donor_variant, coding_sequence_variant	5/62		NM_001378452.1	ENSP00000497605

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

Pathogenic, criteria provided, single submitter

research

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

Nov 14, 2016

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553654413; hg19: chr3-4669560;