rs750473506

Variant names:

• chr3-4675152-A-G
• rs750473506
• NM_001378452.1:c.2683A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.2683A>G​(p.Ile895Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 8.86

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 5 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, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2638A>G	p.Ile880Val	missense_variant	Exon 22 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2638A>G	p.Ile880Val	missense_variant	Exon 22 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2638A>G	p.Ile880Val	missense_variant	Exon 22 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2638A>G	p.Ile880Val	missense_variant	Exon 22 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2638A>G	p.Ile880Val	missense_variant	Exon 20 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2683A>G	p.Ile895Val	missense_variant	Exon 23 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2638A>G	p.Ile880Val	missense_variant	Exon 22 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.520A>G	p.Ile174Val	missense_variant	Exon 4 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.10A>G	p.Ile4Val	missense_variant	Exon 1 of 39			ENSP00000498149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248414 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458030 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 880 of the ITPR1 protein (p.Ile880Val). This variant is present in population databases (rs750473506, gnomAD 0.0009%). This missense change has been observed in individual(s) with congenital ataxia (PMID: 34445196). ClinVar contains an entry for this variant (Variation ID: 586044). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ITPR1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 27, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Aug 22, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic ataxia Pathogenic:1

Jul 12, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.94	N;N;N;N;.;.;.;.;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;.;D;.
Sift4G	Uncertain	0.012	D;D;.;D;.;.;.;.;D;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.73
MutPred		0.70		Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;.;.;
MVP		0.90
MPC		1.6
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750473506; hg19: chr3-4716836;