3-4675201-C-T

Position:

chr3-4675201-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6

The NM_001378452.1(ITPR1):c.2732C>T(p.Ala911Val) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,611,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A911A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

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=0.07862571).

BP6

Variant 3-4675201-C-T is Benign according to our data. Variant chr3-4675201-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345716.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITPR1	NM_001378452.1 linkuse as main transcript	c.2732C>T	p.Ala911Val	missense_variant	23/62	ENST00000649015.2
ITPR1	NM_001168272.2 linkuse as main transcript	c.2687C>T	p.Ala896Val	missense_variant	22/61
ITPR1	NM_001099952.4 linkuse as main transcript	c.2732C>T	p.Ala911Val	missense_variant	23/59
ITPR1	NM_002222.7 linkuse as main transcript	c.2687C>T	p.Ala896Val	missense_variant	22/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.2732C>T	p.Ala911Val	missense_variant	23/62		NM_001378452.1		Q14643-1

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000368

AC:

AN:

247512

Hom.:

AF XY:

0.000380

AC XY:

AN XY:

134292

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000372

Gnomad NFE exome

AF:

0.000675

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000314

AC:

459

AN:

1459730

Hom.:

Cov.:

AF XY:

0.000340

AC XY:

247

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000450

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000363

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000408

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000720

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000529

Hom.:

Bravo

AF:

0.000351

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000314

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29925855, 29232918, 30778698) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 896 of the ITPR1 protein (p.Ala896Val). This variant is present in population databases (rs201519806, gnomAD 0.06%). This missense change has been observed in individual(s) with hereditary spastic pariplegia (PMID: 30778698). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 345716). 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 with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.2687C>T (p.A896V) alteration is located in exon 22 (coding exon 20) of the ITPR1 gene. This alteration results from a C to T substitution at nucleotide position 2687, causing the alanine (A) at amino acid position 896 to be replaced by a valine (V). This variant is unlikely to be causative of spinocerebellar ataxia; however, its contribution to the development of Gillespie syndrome is uncertain. Based on data from the Genome Aggregation Database (gnomAD) database, the ITPR1 c.2687C>T alteration was observed in 0.04% (103/278904) of total alleles studied, with a frequency of 0.07% (86/127962) in the European (non-Finnish) subpopulation. This variant was identified in two families with hereditary spastic paraplegia (Elert-Dobkowska, 2019). This amino acid position is not well conserved in available vertebrate species. The p.A896V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 29

Benign:1

Likely benign, criteria provided, single submitter

research

Schule lab, Hertie Institute for Clinical Brain Research

Feb 09, 2018

- -

Autosomal dominant cerebellar ataxia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

.;.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

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

M_CAP

Benign

0.028

MetaRNN

Benign

0.079

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.14

N;.;.;.;.;.;N;.;.;.

MutationTaster

Benign

0.83

D;D;D;D;N;N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.5

N;N;N;N;.;.;.;.;N;.

REVEL

Benign

0.21

Sift

Benign

0.44

T;T;T;T;.;.;.;.;T;.

Sift4G

Benign

0.37

T;T;.;T;.;.;.;.;T;.

Polyphen

0.69

.;.;.;.;.;.;P;.;.;.

Vest4

0.27

MVP

0.54

MPC

0.76

ClinPred

0.029

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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