rs878853171

Variant names:

• chr3-4706208-C-T
• rs878853171
• NM_001378452.1:c.4699C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001378452.1(ITPR1):​c.4699C>T​(p.Gln1567*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.72
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

LOC124906210 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4706208-C-T is Pathogenic according to our data. Variant chr3-4706208-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 235915.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4699C>T	p.Gln1567*	stop_gained	Exon 37 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4699C>T	p.Gln1567*	stop_gained	Exon 37 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4672C>T	p.Gln1558*	stop_gained	Exon 37 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4672C>T	p.Gln1558*	stop_gained	Exon 37 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4654C>T	p.Gln1552*	stop_gained	Exon 36 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4654C>T	p.Gln1552*	stop_gained	Exon 36 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4627C>T	p.Gln1543*	stop_gained	Exon 34 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4672C>T	p.Gln1558*	stop_gained	Exon 37 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4627C>T	p.Gln1543*	stop_gained	Exon 36 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2509C>T	p.Gln837*	stop_gained	Exon 18 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1999C>T	p.Gln667*	stop_gained	Exon 15 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1606C>T	p.Gln536*	stop_gained	Exon 13 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gillespie syndrome Pathogenic:1

Jul 20, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.7
Vest4		0.98
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878853171; hg19: chr3-4747892;