rs121912425

Variant names:

• chr3-4683472-C-T
• rs121912425
• NM_001378452.1:c.3248C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001378452.1(ITPR1):​c.3248C>T​(p.Pro1083Leu) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 3-4683472-C-T is Pathogenic according to our data. Variant chr3-4683472-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14801.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.3248C>T	p.Pro1083Leu	missense_variant	Exon 27 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3203C>T	p.Pro1068Leu	missense_variant	Exon 26 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3221C>T	p.Pro1074Leu	missense_variant	Exon 27 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3176C>T	p.Pro1059Leu	missense_variant	Exon 26 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3248C>T	p.Pro1083Leu	missense_variant	Exon 27 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3221C>T	p.Pro1074Leu	missense_variant	Exon 27 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3221C>T	p.Pro1074Leu	missense_variant	Exon 27 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3203C>T	p.Pro1068Leu	missense_variant	Exon 26 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3203C>T	p.Pro1068Leu	missense_variant	Exon 26 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3176C>T	p.Pro1059Leu	missense_variant	Exon 24 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3221C>T	p.Pro1074Leu	missense_variant	Exon 27 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3176C>T	p.Pro1059Leu	missense_variant	Exon 26 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1058C>T	p.Pro353Leu	missense_variant	Exon 8 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.548C>T	p.Pro183Leu	missense_variant	Exon 5 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.155C>T	p.Pro52Leu	missense_variant	Exon 3 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Spinocerebellar ataxia type 15/16 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 19, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0050	D;D;.;D;.;.;.;.;D;.
Polyphen		0.97	.;.;.;.;.;.;D;.;.;.
Vest4		0.84
MutPred		0.71		.;.;.;.;.;.;Loss of loop (P = 0.1242);.;.;.;
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.81

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: rs121912425; hg19: chr3-4725156;