rs13079522

chr3-4788048-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):c.6717A>G(p.Thr2239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,611,078 control chromosomes in the GnomAD database, including 82,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7349 hom., cov: 32)
  • Exomes 𝑓: 0.32 (75464 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.89

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 3-4788048-A-G is Benign according to our data. Variant chr3-4788048-A-G is described in ClinVar as [Benign]. Clinvar id is 129301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4788048-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.6717A>G	p.Thr2239=	synonymous_variant	52/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.6672A>G	p.Thr2224=	synonymous_variant	51/61
ITPR1	NM_001099952.4	c.6573A>G	p.Thr2191=	synonymous_variant	49/59
ITPR1	NM_002222.7	c.6528A>G	p.Thr2176=	synonymous_variant	48/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.6717A>G	p.Thr2239=	synonymous_variant	52/62		NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46399 AN: 151972 Hom.: 7342 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.301 AC: 73830 AN: 245388 Hom.: 11831 AF XY: 0.307 AC XY: 40809 AN XY: 132976

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.0941

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.318 AC: 463693 AN: 1458988 Hom.: 75464 Cov.: 32 AF XY: 0.319 AC XY: 231461 AN XY: 725554

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.240

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.336

Gnomad4 FIN exome AF: 0.395

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.305 AC: 46427 AN: 152090 Hom.: 7349 Cov.: 32 AF XY: 0.307 AC XY: 22854 AN XY: 74334

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.408

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.274

Alfa AF: 0.312 Hom.: 5472

Bravo AF: 0.290

Asia WGS AF: 0.213 AC: 738 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Athena Diagnostics	Sep 04, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

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	-0.95
Cadd	Benign	0.54
Dann	Benign	0.45

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: rs13079522; hg19: chr3-4829732; COSMIC: COSV57002458; COSMIC: COSV57002458;