3-4685168-G-A

Position:

chr3-4685168-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_001378452.1(ITPR1):c.3664G>A(p.Ala1222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,606,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.24

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 -4 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). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the 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=0.061921865).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000481 (70/1454718) while in subpopulation AMR AF= 0.000203 (9/44326). AF 95% confidence interval is 0.000105. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.3664G>A	p.Ala1222Thr	missense_variant	30/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.3619G>A	p.Ala1207Thr	missense_variant	29/61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.3637G>A	p.Ala1213Thr	missense_variant	30/59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.3592G>A	p.Ala1198Thr	missense_variant	29/58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.3664G>A	p.Ala1222Thr	missense_variant	30/62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.3637G>A	p.Ala1213Thr	missense_variant	30/62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.3637G>A	p.Ala1213Thr	missense_variant	30/62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.3619G>A	p.Ala1207Thr	missense_variant	29/61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.3619G>A	p.Ala1207Thr	missense_variant	29/61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.3592G>A	p.Ala1198Thr	missense_variant	27/59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.3637G>A	p.Ala1213Thr	missense_variant	30/59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.3592G>A	p.Ala1198Thr	missense_variant	29/58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.1474G>A	p.Ala492Thr	missense_variant	11/42			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.964G>A	p.Ala322Thr	missense_variant	8/39			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.571G>A	p.Ala191Thr	missense_variant	6/39			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000837

AC:

AN:

238972

Hom.:

AF XY:

0.0000616

AC XY:

AN XY:

129970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000820

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1454718

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

723486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000203

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1198 of the ITPR1 protein (p.Ala1198Thr). This variant is present in population databases (rs372881053, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447584). 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. 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	GeneDx	Nov 17, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 10, 2017

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.3592G>A (p.A1198T) alteration is located in exon 29 (coding exon 27) of the ITPR1 gene. This alteration results from a G to A substitution at nucleotide position 3592, causing the alanine (A) at amino acid position 1198 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.54

DEOGEN2

Uncertain

0.53

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

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.86

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

M_CAP

Benign

0.023

MetaRNN

Benign

0.062

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

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-1.7

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

PrimateAI

Uncertain

0.71

PROVEAN

Benign

1.3

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

REVEL

Benign

0.28

Sift

Benign

1.0

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

Sift4G

Benign

0.95

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

Polyphen

0.0010

.;.;.;.;.;.;B;.;.;.

Vest4

0.20

MVP

0.21

MPC

0.70

ClinPred

0.038

GERP RS

4.4

Varity_R

0.032

gMVP

0.081

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