rs863224882

Positions:

• chr3-4645703-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001378452.1(ITPR1):​c.830G>T​(p.Ser277Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.89

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• PP5: Variant 3-4645703-G-T is Pathogenic according to our data. Variant chr3-4645703-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216945.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-4645703-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.830G>T	p.Ser277Ile	missense_variant	10/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.830G>T	p.Ser277Ile	missense_variant	10/61		NP_001161744.1
ITPR1	NM_001099952.4	c.830G>T	p.Ser277Ile	missense_variant	10/59		NP_001093422.2
ITPR1	NM_002222.7	c.830G>T	p.Ser277Ile	missense_variant	10/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.830G>T	p.Ser277Ile	missense_variant	10/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.830G>T	p.Ser277Ile	missense_variant	10/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.830G>T	p.Ser277Ile	missense_variant	10/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.830G>T	p.Ser277Ile	missense_variant	10/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.830G>T	p.Ser277Ile	missense_variant	10/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.830G>T	p.Ser277Ile	missense_variant	8/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.830G>T	p.Ser277Ile	missense_variant	10/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.830G>T	p.Ser277Ile	missense_variant	10/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Oct 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.88
MutPred		0.56		Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.93

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

Other links and lift over

dbSNP: rs863224882; hg19: chr3-4687387;