rs1553686424

Positions:

• chr3-4674222-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.

Transcripts

RefSeq

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

Ensembl

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

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

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;.;.;.
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

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