rs753499808

Variant names:

• chr3-4800535-A-G
• rs753499808
• NM_001378452.1:c.7042A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378452.1(ITPR1):​c.7042A>G​(p.Thr2348Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.88

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 Uncertain_significance. Variant got 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3210718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7042A>G	p.Thr2348Ala	missense_variant	Exon 54 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6997A>G	p.Thr2333Ala	missense_variant	Exon 53 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6898A>G	p.Thr2300Ala	missense_variant	Exon 51 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.6853A>G	p.Thr2285Ala	missense_variant	Exon 50 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7042A>G	p.Thr2348Ala	missense_variant	Exon 54 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7018A>G	p.Thr2340Ala	missense_variant	Exon 54 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7015A>G	p.Thr2339Ala	missense_variant	Exon 54 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7000A>G	p.Thr2334Ala	missense_variant	Exon 53 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6997A>G	p.Thr2333Ala	missense_variant	Exon 53 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6970A>G	p.Thr2324Ala	missense_variant	Exon 51 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6898A>G	p.Thr2300Ala	missense_variant	Exon 51 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6853A>G	p.Thr2285Ala	missense_variant	Exon 50 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4804A>G	p.Thr1602Ala	missense_variant	Exon 34 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4219A>G	p.Thr1407Ala	missense_variant	Exon 31 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3982A>G	p.Thr1328Ala	missense_variant	Exon 31 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249270 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135240

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jan 20, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 586054). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITPR1 protein function. This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is present in population databases (rs753499808, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2285 of the ITPR1 protein (p.Thr2285Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.033
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.044	D
MutationAssessor	Benign	1.7	.;.;.;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;D;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.52	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.28	T;T;.;T;.;.;.;.;T;.
Polyphen		0.013	.;.;.;.;.;.;B;.;.;.
Vest4		0.46
MutPred		0.34		.;.;.;.;.;.;Gain of methylation at R2351 (P = 0.0904);.;.;.;
MVP		0.85
MPC		0.87
ClinPred		0.49	T
GERP RS		5.1
Varity_R		0.20
gMVP		0.80

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: rs753499808; hg19: chr3-4842219;