NM_001378452.1:c.2455G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001378452.1(ITPR1):c.2455G>A(p.Asp819Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,600,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 missense, splice_region

Scores

Splicing: ADA: 0.9574

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]

ITPR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 20 of 61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 20 of 58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 20 of 61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 20 of 61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 18 of 59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.2455G>A	p.Asp819Asn	missense_variant, splice_region_variant	Exon 21 of 59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.2410G>A	p.Asp804Asn	missense_variant, splice_region_variant	Exon 20 of 58	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.292G>A	p.Asp98Asn	missense_variant, splice_region_variant	Exon 2 of 42			ENSP00000497872.1	A0A3B3ITQ1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000291

AC:

AN:

240924

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.000103

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.00000759

AC:

AN:

1448418

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

718154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000760

Gnomad4 SAS exome

AF:

0.0000353

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000593

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000331

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.60

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

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

M;.;.;.;.;.;M;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.2

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

REVEL

Uncertain

0.58

Sift

Uncertain

0.011

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.31

Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;.;.;

MVP

0.89

MPC

1.0

ClinPred

0.81

GERP RS

5.0

Varity_R

0.45

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Benign

0.59

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over