rs535969136

Variant names:

• chr3-4768574-C-A
• rs535969136
• NM_001378452.1:c.5789C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001378452.1(ITPR1):​c.5789C>A​(p.Ala1930Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,976 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.98

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 0 ACMG points.

• 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=0.38073987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5789C>A	p.Ala1930Asp	missense_variant	Exon 46 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5744C>A	p.Ala1915Asp	missense_variant	Exon 45 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5645C>A	p.Ala1882Asp	missense_variant	Exon 43 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5600C>A	p.Ala1867Asp	missense_variant	Exon 42 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5789C>A	p.Ala1930Asp	missense_variant	Exon 46 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5765C>A	p.Ala1922Asp	missense_variant	Exon 46 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5762C>A	p.Ala1921Asp	missense_variant	Exon 46 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5747C>A	p.Ala1916Asp	missense_variant	Exon 45 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5744C>A	p.Ala1915Asp	missense_variant	Exon 45 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5717C>A	p.Ala1906Asp	missense_variant	Exon 43 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5645C>A	p.Ala1882Asp	missense_variant	Exon 43 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5600C>A	p.Ala1867Asp	missense_variant	Exon 42 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3551C>A	p.Ala1184Asp	missense_variant	Exon 26 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3089C>A	p.Ala1030Asp	missense_variant	Exon 24 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2696C>A	p.Ala899Asp	missense_variant	Exon 22 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249084 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000302

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

Nov 20, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1867 of the ITPR1 protein (p.Ala1867Asp). This variant is present in population databases (rs535969136, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 586051). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.28	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.076	T;T;.;T;.;.;.;.;T;.
Polyphen		0.41	.;.;.;.;.;.;B;.;.;.
Vest4		0.62
MutPred		0.34		.;.;.;.;.;.;Loss of MoRF binding (P = 0.061);.;.;.;
MVP		0.79
MPC		0.54
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs535969136; hg19: chr3-4810258;