NM_001378452.1:c.6349G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_001378452.1(ITPR1):​c.6349G>A​(p.Ala2117Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2117S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.91
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 Uncertain_significance. Variant got 2 ACMG points.

PP2
Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITPR1NM_001378452.1 linkc.6349G>A p.Ala2117Thr missense_variant Exon 49 of 62 ENST00000649015.2 NP_001365381.1
ITPR1NM_001168272.2 linkc.6304G>A p.Ala2102Thr missense_variant Exon 48 of 61 NP_001161744.1 Q14643-2
ITPR1NM_001099952.4 linkc.6205G>A p.Ala2069Thr missense_variant Exon 46 of 59 NP_001093422.2 Q14643-3B4DER3Q59H91
ITPR1NM_002222.7 linkc.6160G>A p.Ala2054Thr missense_variant Exon 45 of 58 NP_002213.5 Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITPR1ENST00000649015.2 linkc.6349G>A p.Ala2117Thr missense_variant Exon 49 of 62 NM_001378452.1 ENSP00000497605.1 Q14643-1
ITPR1ENST00000354582.12 linkc.6325G>A p.Ala2109Thr missense_variant Exon 49 of 62 5 ENSP00000346595.8 A0A3F2YNW8
ITPR1ENST00000648266.1 linkc.6322G>A p.Ala2108Thr missense_variant Exon 49 of 62 ENSP00000498014.1 A0A3B3IU04
ITPR1ENST00000650294.1 linkc.6307G>A p.Ala2103Thr missense_variant Exon 48 of 61 ENSP00000498056.1 A0A3B3ITU8
ITPR1ENST00000443694.5 linkc.6304G>A p.Ala2102Thr missense_variant Exon 48 of 61 1 ENSP00000401671.2 Q14643-2
ITPR1ENST00000648309.1 linkc.6277G>A p.Ala2093Thr missense_variant Exon 46 of 59 ENSP00000497026.1 Q14643-5
ITPR1ENST00000357086.10 linkc.6205G>A p.Ala2069Thr missense_variant Exon 46 of 59 1 ENSP00000349597.4 Q14643-3
ITPR1ENST00000456211.8 linkc.6160G>A p.Ala2054Thr missense_variant Exon 45 of 58 1 ENSP00000397885.2 Q14643-4
ITPR1ENST00000648038.1 linkc.4111G>A p.Ala1371Thr missense_variant Exon 29 of 42 ENSP00000497872.1 A0A3B3ITQ1
ITPR1ENST00000648431.1 linkc.3649G>A p.Ala1217Thr missense_variant Exon 27 of 39 ENSP00000498149.1 A0A3B3IU05
ITPR1ENST00000648212.1 linkc.3256G>A p.Ala1086Thr missense_variant Exon 25 of 39 ENSP00000498022.1 A0A3B3IU13

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1459922
Hom.:
0
Cov.:
29
AF XY:
0.00000551
AC XY:
4
AN XY:
726322
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000720
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000205
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.88
.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;.;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
3.0
.;.;.;.;.;.;M;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.9
D;D;.;D;.;.;.;.;D;.
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0030
D;D;.;D;.;.;.;.;D;.
Sift4G
Uncertain
0.0060
D;D;.;D;.;.;.;.;D;.
Polyphen
0.99
.;.;.;.;.;.;D;.;.;.
Vest4
0.93
MVP
0.78
MPC
1.4
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.69
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs373973399; hg19: chr3-4821291; COSMIC: COSV56967721; COSMIC: COSV56967721; API