rs1553758021

Variant names:

• chr3-4815144-T-A
• rs1553758021
• NM_001378452.1:c.7793T>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4815144-T-A
• chr3-4815144-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.7793T>A​(p.Ile2598Asn) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2598T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.95
• Publications: 3 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 9 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, 1 uncertain in NM_001378452.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4815144-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 559630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 3-4815144-T-A is Pathogenic according to our data. Variant chr3-4815144-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 522562.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.7793T>A	p.Ile2598Asn	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.7793T>A	p.Ile2598Asn	missense_variant	Exon 59 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7769T>A	p.Ile2590Asn	missense_variant	Exon 59 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7766T>A	p.Ile2589Asn	missense_variant	Exon 59 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7751T>A	p.Ile2584Asn	missense_variant	Exon 58 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7748T>A	p.Ile2583Asn	missense_variant	Exon 58 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7721T>A	p.Ile2574Asn	missense_variant	Exon 56 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7649T>A	p.Ile2550Asn	missense_variant	Exon 56 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7604T>A	p.Ile2535Asn	missense_variant	Exon 55 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5555T>A	p.Ile1852Asn	missense_variant	Exon 39 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4970T>A	p.Ile1657Asn	missense_variant	Exon 36 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4733T>A	p.Ile1578Asn	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

Apr 18, 2018

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	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;.;.;H;.;.;.;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.6	D;D;.;D;.;N;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.51		.;.;.;.;.;.;.;Loss of stability (P = 0.0434);.;.;.;.;.;.;
MVP		0.92
MPC		2.6
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		1.0
Mutation Taster		=0/100	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: rs1553758021; hg19: chr3-4856828;