rs1553686424

Variant names:

• chr3-4674222-C-T
• rs1553686424
• NM_001378452.1:c.2477C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378452.1(ITPR1):​c.2477C>T​(p.Ser826Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2432C>T	p.Ser811Phe	missense_variant	Exon 21 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2432C>T	p.Ser811Phe	missense_variant	Exon 21 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2432C>T	p.Ser811Phe	missense_variant	Exon 21 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2432C>T	p.Ser811Phe	missense_variant	Exon 21 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2432C>T	p.Ser811Phe	missense_variant	Exon 19 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2477C>T	p.Ser826Phe	missense_variant	Exon 22 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2432C>T	p.Ser811Phe	missense_variant	Exon 21 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.314C>T	p.Ser105Phe	missense_variant	Exon 3 of 42			ENSP00000497872.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical behavior;C0026650:Movement disorder;C0234518:Slurred speech;C1843885:Progressive gait ataxia Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;.;M;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;D;D;D;.;.;.;.;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;D;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Polyphen		0.60	.;.;.;.;.;.;P;.;.;.
Vest4		0.42
MutPred		0.27		Loss of phosphorylation at S826 (P = 0.0259);.;Loss of phosphorylation at S826 (P = 0.0259);.;Loss of phosphorylation at S826 (P = 0.0259);.;Loss of phosphorylation at S826 (P = 0.0259);.;.;.;
MVP		0.86
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.78
Mutation Taster		=68/32	polymorphism

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: rs1553686424; hg19: chr3-4715906; COSMIC: COSV105880211; COSMIC: COSV105880211;