rs878853176

Variant names:

• chr3-4815154-T-G
• rs878853176
• NM_001378452.1:c.7803T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001378452.1(ITPR1):​c.7803T>G​(p.Phe2601Leu) variant causes a missense change involving the alteration of a non-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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.692
• Publications: 4 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001378452.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 3-4815154-T-G is Pathogenic according to our data. Variant chr3-4815154-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 235920.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.7803T>G	p.Phe2601Leu	missense_variant	Exon 59 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7803T>G	p.Phe2601Leu	missense_variant	Exon 59 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7779T>G	p.Phe2593Leu	missense_variant	Exon 59 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7776T>G	p.Phe2592Leu	missense_variant	Exon 59 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7761T>G	p.Phe2587Leu	missense_variant	Exon 58 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7758T>G	p.Phe2586Leu	missense_variant	Exon 58 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7731T>G	p.Phe2577Leu	missense_variant	Exon 56 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7659T>G	p.Phe2553Leu	missense_variant	Exon 56 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7614T>G	p.Phe2538Leu	missense_variant	Exon 55 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5565T>G	p.Phe1855Leu	missense_variant	Exon 39 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4980T>G	p.Phe1660Leu	missense_variant	Exon 36 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4743T>G	p.Phe1581Leu	missense_variant	Exon 36 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;M;.;.;.;.;.;.
PhyloP100		0.69
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.7	D;D;.;D;.;N;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.92
MutPred		0.28		.;.;.;.;.;.;.;Gain of disorder (P = 0.1414);.;.;.;.;.;.;
MVP		0.95
MPC		2.1
ClinPred		0.98	D
GERP RS		1.0
Varity_R		0.89
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878853176; hg19: chr3-4856838;