rs556943368

Positions:

• chr3-4691227-C-G
• chr3-4691227-C-T

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.3912C>G​(p.His1304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.24

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, 0.885
• PP5: Variant 3-4691227-C-G is Pathogenic according to our data. Variant chr3-4691227-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496612.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.3912C>G	p.His1304Gln	missense_variant	32/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3867C>G	p.His1289Gln	missense_variant	31/61		NP_001161744.1
ITPR1	NM_001099952.4	c.3885C>G	p.His1295Gln	missense_variant	32/59		NP_001093422.2
ITPR1	NM_002222.7	c.3840C>G	p.His1280Gln	missense_variant	31/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3912C>G	p.His1304Gln	missense_variant	32/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3885C>G	p.His1295Gln	missense_variant	32/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3885C>G	p.His1295Gln	missense_variant	32/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3867C>G	p.His1289Gln	missense_variant	31/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3867C>G	p.His1289Gln	missense_variant	31/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3840C>G	p.His1280Gln	missense_variant	29/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3885C>G	p.His1295Gln	missense_variant	32/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3840C>G	p.His1280Gln	missense_variant	31/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1722C>G	p.His574Gln	missense_variant	13/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1212C>G	p.His404Gln	missense_variant	10/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.819C>G	p.His273Gln	missense_variant	8/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460762 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Oct 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Benign	0.084	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.11	T;T;.;T;.;.;.;.;T;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.92
MutPred		0.69		.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;
MVP		0.93
MPC		1.8
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.64
gMVP		0.72

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: rs556943368; hg19: chr3-4732911;