rs878853173

Positions:

• chr3-4782744-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001378452.1(ITPR1):​c.6510+3A>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4782744-A-T is Pathogenic according to our data. Variant chr3-4782744-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 235917.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-4782744-A-T is described in Lovd as [Likely_pathogenic]. Variant chr3-4782744-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6510+3A>T		splice_donor_region_variant, intron_variant		ENST00000649015.2	NP_001365381.1
ITPR1	NM_001099952.4	c.6366+3A>T		splice_donor_region_variant, intron_variant			NP_001093422.2
ITPR1	NM_001168272.2	c.6465+3A>T		splice_donor_region_variant, intron_variant			NP_001161744.1
ITPR1	NM_002222.7	c.6321+3A>T		splice_donor_region_variant, intron_variant			NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6510+3A>T		splice_donor_region_variant, intron_variant			NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gillespie syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853173; hg19: chr3-4824428;