rs535969136

Positions:

• chr3-4768574-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001378452.1(ITPR1):​c.5789C>A​(p.Ala1930Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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=0.38073987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5789C>A	p.Ala1930Asp	missense_variant	46/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5744C>A	p.Ala1915Asp	missense_variant	45/61		NP_001161744.1
ITPR1	NM_001099952.4	c.5645C>A	p.Ala1882Asp	missense_variant	43/59		NP_001093422.2
ITPR1	NM_002222.7	c.5600C>A	p.Ala1867Asp	missense_variant	42/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5789C>A	p.Ala1930Asp	missense_variant	46/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5765C>A	p.Ala1922Asp	missense_variant	46/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5762C>A	p.Ala1921Asp	missense_variant	46/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5747C>A	p.Ala1916Asp	missense_variant	45/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5744C>A	p.Ala1915Asp	missense_variant	45/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5717C>A	p.Ala1906Asp	missense_variant	43/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5645C>A	p.Ala1882Asp	missense_variant	43/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5600C>A	p.Ala1867Asp	missense_variant	42/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3551C>A	p.Ala1184Asp	missense_variant	26/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3089C>A	p.Ala1030Asp	missense_variant	24/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2696C>A	p.Ala899Asp	missense_variant	22/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249084 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

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: 0.000473

Bravo AF: 0.0000302

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.28	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.076	T;T;.;T;.;.;.;.;T;.
Polyphen		0.41	.;.;.;.;.;.;B;.;.;.
Vest4		0.62
MutPred		0.34		.;.;.;.;.;.;Loss of MoRF binding (P = 0.061);.;.;.;
MVP		0.79
MPC		0.54
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.36
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs535969136; hg19: chr3-4810258;