rs41289636

chr3-4673157-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001378452.1(ITPR1):c.2226G>A(p.Ala742=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,746 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (42 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.83

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-4673157-G-A is Benign according to our data. Variant chr3-4673157-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4673157-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.2226G>A	p.Ala742=	synonymous_variant	21/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.2181G>A	p.Ala727=	synonymous_variant	20/61
ITPR1	NM_001099952.4	c.2226G>A	p.Ala742=	synonymous_variant	21/59
ITPR1	NM_002222.7	c.2181G>A	p.Ala727=	synonymous_variant	20/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.2226G>A	p.Ala742=	synonymous_variant	21/62		NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00683

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00443 AC: 1101 AN: 248464 Hom.: 3 AF XY: 0.00457 AC XY: 616 AN XY: 134840

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00641 AC: 9372 AN: 1461450 Hom.: 42 Cov.: 31 AF XY: 0.00621 AC XY: 4517 AN XY: 726992

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.00770

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00458 AC: 697 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74474

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00684

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00540 Hom.: 0

Bravo AF: 0.00541

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00797

EpiControl AF: 0.00884

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ITPR1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 04, 2019	- -

ITPR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.4
Dann	Benign	0.79

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: rs41289636; hg19: chr3-4714841;