rs1553757628

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001378452.1(ITPR1):c.7648G>A(p.Gly2550Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 9.52

Variant links:

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 links:

ENSG00000235978 (HGNC:):

ENSG00000235978 links:

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ACMG classification

Classification made for transcript

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, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.7648G>A	p.Gly2550Arg	missense_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.7648G>A	p.Gly2550Arg	missense_variant	Exon 58 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.7624G>A	p.Gly2542Arg	missense_variant	Exon 58 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.7621G>A	p.Gly2541Arg	missense_variant	Exon 58 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.7606G>A	p.Gly2536Arg	missense_variant	Exon 57 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.7603G>A	p.Gly2535Arg	missense_variant	Exon 57 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.7576G>A	p.Gly2526Arg	missense_variant	Exon 55 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.7504G>A	p.Gly2502Arg	missense_variant	Exon 55 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.7459G>A	p.Gly2487Arg	missense_variant	Exon 54 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.5410G>A	p.Gly1804Arg	missense_variant	Exon 38 of 42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.4825G>A	p.Gly1609Arg	missense_variant	Exon 35 of 39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.4588G>A	p.Gly1530Arg	missense_variant	Exon 35 of 39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727082

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Sep 11, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34758253) -

Apr 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 expected to disrupt ITPR1 protein function. ClinVar contains an entry for this variant (Variation ID: 520945). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2487 of the ITPR1 protein (p.Gly2487Arg). -

Spinocerebellar ataxia type 29

Pathogenic:1

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Mar 15, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;.;.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;.;.;.;.;.;.;H;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.8

D;D;.;D;.;D;.;.;.;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;.;D;.;D;.;.;.;D;.

Sift4G

Pathogenic

0.0010

D;D;.;D;.;D;.;.;.;D;.

Polyphen

1.0

.;.;.;.;.;D;.;D;.;.;.

Vest4

0.97

MutPred

0.72

.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0508);.;.;.;

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

4.9

Varity_R

0.93

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over