rs1085308010

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001378452.1(ITPR1):c.731A>C(p.His244Pro) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H244R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.22

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001378452.1

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-4645604-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 3-4645604-A-C is Pathogenic according to our data. Variant chr3-4645604-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522002.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ITPR1	NM_001378452.1 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ITPR1	ENST00000649015.2 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1 link	c.731A>C	p.His244Pro	missense_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8 link	c.731A>C	p.His244Pro	missense_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Jan 23, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.731A>C (p.H244P) alteration is located in exon 10 (coding exon 8) of the ITPR1 gene. This alteration results from an A to C substitution at nucleotide position 731, causing the histidine (H) at amino acid position 244 to be replaced by a proline (P)._x000D_ _x000D_ for ITPR1-related congenital non-progressive spinocerebellar ataxia (SCA29); however, its clinical significance for Gillespie syndrome is uncertain and it is unlikely to be causative of ITPR1-related spinocerebellar ataxia (SCA15). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M;.;.;M;.;.;.;M;M;M

PhyloP100

9.2

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-9.3

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.99, 1.0

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

Vest4

0.97

MutPred

0.85

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

0.99

MPC

2.2

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.99

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over