rs797045632

Positions:

• chr3-4670896-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.2174A>C​(p.Lys725Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,166 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: 6.9e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.14

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]

ITPR1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25788748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2174A>C	p.Lys725Thr	missense_variant	20/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2129A>C	p.Lys710Thr	missense_variant	19/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2174A>C	p.Lys725Thr	missense_variant	20/59		NP_001093422.2
ITPR1	NM_002222.7	c.2129A>C	p.Lys710Thr	missense_variant	19/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2174A>C	p.Lys725Thr	missense_variant	20/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2174A>C	p.Lys725Thr	missense_variant	20/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2174A>C	p.Lys725Thr	missense_variant	20/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2129A>C	p.Lys710Thr	missense_variant	19/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2129A>C	p.Lys710Thr	missense_variant	19/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2129A>C	p.Lys710Thr	missense_variant	17/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2174A>C	p.Lys725Thr	missense_variant	20/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2129A>C	p.Lys710Thr	missense_variant	19/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.11A>C	p.Lys4Thr	missense_variant	1/42			ENSP00000497872.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 718254

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2022	Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with autosomal dominant spinocerebellar ataxia. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2023	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. ClinVar contains an entry for this variant (Variation ID: 211213). This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 29915382). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 710 of the ITPR1 protein (p.Lys710Thr). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L;.;.;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D;D;D;.;.;.;.;D;.
REVEL	Uncertain	0.31
Sift	Benign	0.22	T;T;T;T;.;.;.;.;T;.
Sift4G	Benign	0.32	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0030	.;.;.;.;.;.;B;.;.;.
Vest4		0.62
MutPred		0.29		Loss of ubiquitination at K725 (P = 0.013);.;Loss of ubiquitination at K725 (P = 0.013);.;Loss of ubiquitination at K725 (P = 0.013);.;Loss of ubiquitination at K725 (P = 0.013);.;.;.;
MVP		0.79
MPC		0.87
ClinPred		0.64	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.70

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: rs797045632; hg19: chr3-4712580;