rs752281590

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_StrongPM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001378452.1(ITPR1):c.7660G>A(p.Gly2554Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2554W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 25 ACMG points.

PS1

Transcript NM_001378452.1 (ITPR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 235923

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-4814522-G-T is described in Lovd as [Likely_pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 3-4814521-G-A is Pathogenic according to our data. Variant chr3-4814521-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4814521-G-A is described in Lovd as [Pathogenic]. Variant chr3-4814521-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1 linkuse as main transcript	c.7660G>A	p.Gly2554Arg	missense_variant	58/62	ENST00000649015.2
LOC124906209	XR_007095795.1 linkuse as main transcript	n.725-90C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.7660G>A	p.Gly2554Arg	missense_variant	58/62		NM_001378452.1		Q14643-1
	ENST00000693140.1 linkuse as main transcript	n.581+11225C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249244

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

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:

6.84e-7

AC:

AN:

1461358

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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.:

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gillespie syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 20, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 09, 2018	PS3,PM6,PP2,PP3 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27108798, 28191889, 31692161, 28659154, 28135719, 28628100, 32499604, 25533962) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -

Anterior segment dysgenesis

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Eye Genetics Research Group, Children's Medical Research Institute

Mar 31, 2020

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2016

- -

Spinocerebellar ataxia type 29

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.99

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

0.89

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.8

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.81

.;.;.;.;.;.;.;Gain of solvent accessibility (P = 6e-04);.;.;.;

MVP

0.97

MPC

2.2

ClinPred

1.0

GERP RS

4.9

Varity_R

0.89

gMVP

0.99

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