3-4685168-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

3
16

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]

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
ITPR1NM_001378452.1 linkc.3664G>A p.Ala1222Thr missense_variant 30/62 ENST00000649015.2 NP_001365381.1
ITPR1NM_001168272.2 linkc.3619G>A p.Ala1207Thr missense_variant 29/61 NP_001161744.1 Q14643-2
ITPR1NM_001099952.4 linkc.3637G>A p.Ala1213Thr missense_variant 30/59 NP_001093422.2 Q14643-3B4DER3Q59H91
ITPR1NM_002222.7 linkc.3592G>A p.Ala1198Thr missense_variant 29/58 NP_002213.5 Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ITPR1ENST00000649015.2 linkc.3664G>A p.Ala1222Thr missense_variant 30/62 NM_001378452.1 ENSP00000497605.1 Q14643-1
ITPR1ENST00000354582.12 linkc.3637G>A p.Ala1213Thr missense_variant 30/625 ENSP00000346595.8 A0A3F2YNW8
ITPR1ENST00000648266.1 linkc.3637G>A p.Ala1213Thr missense_variant 30/62 ENSP00000498014.1 A0A3B3IU04
ITPR1ENST00000650294.1 linkc.3619G>A p.Ala1207Thr missense_variant 29/61 ENSP00000498056.1 A0A3B3ITU8
ITPR1ENST00000443694.5 linkc.3619G>A p.Ala1207Thr missense_variant 29/611 ENSP00000401671.2 Q14643-2
ITPR1ENST00000648309.1 linkc.3592G>A p.Ala1198Thr missense_variant 27/59 ENSP00000497026.1 Q14643-5
ITPR1ENST00000357086.10 linkc.3637G>A p.Ala1213Thr missense_variant 30/591 ENSP00000349597.4 Q14643-3
ITPR1ENST00000456211.8 linkc.3592G>A p.Ala1198Thr missense_variant 29/581 ENSP00000397885.2 Q14643-4
ITPR1ENST00000648038.1 linkc.1474G>A p.Ala492Thr missense_variant 11/42 ENSP00000497872.1 A0A3B3ITQ1
ITPR1ENST00000648431.1 linkc.964G>A p.Ala322Thr missense_variant 8/39 ENSP00000498149.1 A0A3B3IU05
ITPR1ENST00000648212.1 linkc.571G>A p.Ala191Thr missense_variant 6/39 ENSP00000498022.1 A0A3B3IU13

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152252
Hom.:
0
Cov.:
33
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:
20
AN:
238972
Hom.:
0
AF XY:
0.0000616
AC XY:
8
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:
70
AN:
1454718
Hom.:
0
Cov.:
31
AF XY:
0.0000359
AC XY:
26
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:
7
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
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.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000744
AC:
9

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 22, 2023This 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 submitterclinical testingGeneDxNov 17, 2022In 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 submitterclinical testingAthena DiagnosticsFeb 10, 2017- -
Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 12, 2023The 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
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
21
DANN
Benign
0.54
DEOGEN2
Uncertain
0.53
.;.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.11
N
LIST_S2
Uncertain
0.86
D;D;D;D;D;D;D;D;.;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.062
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
-1.7
.;.;.;.;.;.;N;.;.;.
PrimateAI
Uncertain
0.71
T
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
T
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.

Other links and lift over

dbSNP: rs372881053; hg19: chr3-4726852; COSMIC: COSV56982426; API