3-4815144-T-C

Position:

• chr3-4815144-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.7793T>C​(p.Ile2598Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.95

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]

ENSG00000235978 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 3-4815144-T-C is Pathogenic according to our data. Variant chr3-4815144-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7793T>C	p.Ile2598Thr	missense_variant	59/62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7793T>C	p.Ile2598Thr	missense_variant	59/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7769T>C	p.Ile2590Thr	missense_variant	59/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7766T>C	p.Ile2589Thr	missense_variant	59/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7751T>C	p.Ile2584Thr	missense_variant	58/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7748T>C	p.Ile2583Thr	missense_variant	58/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7721T>C	p.Ile2574Thr	missense_variant	56/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7649T>C	p.Ile2550Thr	missense_variant	56/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7604T>C	p.Ile2535Thr	missense_variant	55/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5555T>C	p.Ile1852Thr	missense_variant	39/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4970T>C	p.Ile1657Thr	missense_variant	36/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4733T>C	p.Ile1578Thr	missense_variant	36/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 11, 2021	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28659154, 33163565, 29997391) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 11, 2022	- -

ITPR1-associated cerebellar ataxia spectrum disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Dec 15, 2017

- -

Spinocerebellar ataxia type 29 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jan 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.7	D;D;.;D;.;N;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.94
MutPred		0.52		.;.;.;.;.;.;.;Loss of stability (P = 0.0105);.;.;.;.;.;.;
MVP		0.95
MPC		2.2
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1553758021; hg19: chr3-4856828;