3-4811344-T-C

Position:

• chr3-4811344-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001378452.1(ITPR1):​c.7352T>C​(p.Leu2451Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.92

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 Likely_pathogenic. Variant got 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 3-4811344-T-C is Pathogenic according to our data. Variant chr3-4811344-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 503525.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7352T>C	p.Leu2451Pro	missense_variant	56/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.7307T>C	p.Leu2436Pro	missense_variant	55/61		NP_001161744.1
ITPR1	NM_001099952.4	c.7208T>C	p.Leu2403Pro	missense_variant	53/59		NP_001093422.2
ITPR1	NM_002222.7	c.7163T>C	p.Leu2388Pro	missense_variant	52/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7352T>C	p.Leu2451Pro	missense_variant	56/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7328T>C	p.Leu2443Pro	missense_variant	56/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7325T>C	p.Leu2442Pro	missense_variant	56/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7310T>C	p.Leu2437Pro	missense_variant	55/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7307T>C	p.Leu2436Pro	missense_variant	55/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7280T>C	p.Leu2427Pro	missense_variant	53/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7208T>C	p.Leu2403Pro	missense_variant	53/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7163T>C	p.Leu2388Pro	missense_variant	52/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5114T>C	p.Leu1705Pro	missense_variant	36/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4529T>C	p.Leu1510Pro	missense_variant	33/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4292T>C	p.Leu1431Pro	missense_variant	33/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Schule lab, Hertie Institute for Clinical Brain Research

Feb 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.7	D;D;.;D;.;N;.;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;.;D;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;.;D;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.
Vest4		0.96
MutPred		0.65		.;.;.;.;.;.;.;Loss of stability (P = 0.0152);.;.;.;
MVP		1.0
MPC		2.5
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

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: rs1553756062; hg19: chr3-4853028;