3-4516546-G-A

Position:

• chr3-4516546-G-A

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.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,774 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ: 5.5951 (greater than the threshold 3.09). Trascript score misZ: 6.2026 (greater than threshold 3.09). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.55G>A	p.Ala19Thr	missense_variant	3/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.55G>A	p.Ala19Thr	missense_variant	3/61		NP_001161744.1
ITPR1	NM_001099952.4	c.55G>A	p.Ala19Thr	missense_variant	3/59		NP_001093422.2
ITPR1	NM_002222.7	c.55G>A	p.Ala19Thr	missense_variant	3/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.55G>A	p.Ala19Thr	missense_variant	3/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.55G>A	p.Ala19Thr	missense_variant	3/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.55G>A	p.Ala19Thr	missense_variant	3/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.55G>A	p.Ala19Thr	missense_variant	3/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.55G>A	p.Ala19Thr	missense_variant	3/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.55G>A	p.Ala19Thr	missense_variant	1/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.55G>A	p.Ala19Thr	missense_variant	3/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.55G>A	p.Ala19Thr	missense_variant	3/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241762 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000311

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: 0.00000207 AC: 3 AN: 1452774 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 722600

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

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.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 19 of the ITPR1 protein (p.Ala19Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. 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. 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	0.73
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;D;.;D;D;.;N;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Benign	0.20	T;T;.;T;T;.;T;.;.;.;T
Sift4G	Benign	0.22	T;T;.;.;T;.;T;.;.;.;T
Polyphen		1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.56
MutPred		0.79		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.91
MPC		1.8
ClinPred		0.83	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.60

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: rs1319285632; hg19: chr3-4558230; COSMIC: COSV56983880;