rs750473506

Positions:

• chr3-4675152-A-G

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.2683A>G​(p.Ile895Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,030 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 8.86

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 6 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, 0.863
• PP5: Variant 3-4675152-A-G is Pathogenic according to our data. Variant chr3-4675152-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586044.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2683A>G	p.Ile895Val	missense_variant	23/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2638A>G	p.Ile880Val	missense_variant	22/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2683A>G	p.Ile895Val	missense_variant	23/59		NP_001093422.2
ITPR1	NM_002222.7	c.2638A>G	p.Ile880Val	missense_variant	22/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2683A>G	p.Ile895Val	missense_variant	23/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2683A>G	p.Ile895Val	missense_variant	23/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2683A>G	p.Ile895Val	missense_variant	23/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2638A>G	p.Ile880Val	missense_variant	22/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2638A>G	p.Ile880Val	missense_variant	22/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2638A>G	p.Ile880Val	missense_variant	20/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2683A>G	p.Ile895Val	missense_variant	23/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2638A>G	p.Ile880Val	missense_variant	22/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.520A>G	p.Ile174Val	missense_variant	4/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.10A>G	p.Ile4Val	missense_variant	1/39			ENSP00000498149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248414 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458030 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725562

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2018	- -

Spastic ataxia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.94	N;N;N;N;.;.;.;.;N;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;.;D;.
Sift4G	Uncertain	0.012	D;D;.;D;.;.;.;.;D;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.73
MutPred		0.70		Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;Gain of ubiquitination at K890 (P = 0.1103);.;.;.;
MVP		0.90
MPC		1.6
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750473506; hg19: chr3-4716836;