rs182840163

chr3-4691209-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001378452.1(ITPR1):c.3894C>T(p.Asn1298=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,613,126 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0220

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 3-4691209-C-T is Benign according to our data. Variant chr3-4691209-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 289460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.022 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.3894C>T	p.Asn1298=	synonymous_variant	32/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.3849C>T	p.Asn1283=	synonymous_variant	31/61
ITPR1	NM_001099952.4	c.3867C>T	p.Asn1289=	synonymous_variant	32/59
ITPR1	NM_002222.7	c.3822C>T	p.Asn1274=	synonymous_variant	31/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.3894C>T	p.Asn1298=	synonymous_variant	32/62		NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000531 AC: 132 AN: 248364 Hom.: 1 AF XY: 0.000379 AC XY: 51 AN XY: 134682

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1460888 Hom.: 2 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 726660

Gnomad4 AFR exome AF: 0.00816

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74432

Gnomad4 AFR AF: 0.00770

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00256

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ITPR1: BP4, BP7 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 13, 2020	- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinocerebellar ataxia type 15/16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	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: rs182840163; hg19: chr3-4732893;