chr3-4800547-C-T

Position:

• chr3-4800547-C-T

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.7054C>T​(p.Leu2352Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,613,528 control chromosomes in the GnomAD database, including 66,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5109 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61376 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0270

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-4800547-C-T is Benign according to our data. Variant chr3-4800547-C-T is described in ClinVar as [Benign]. Clinvar id is 129302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4800547-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7054C>T	p.Leu2352Leu	synonymous_variant	54/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.7009C>T	p.Leu2337Leu	synonymous_variant	53/61		NP_001161744.1
ITPR1	NM_001099952.4	c.6910C>T	p.Leu2304Leu	synonymous_variant	51/59		NP_001093422.2
ITPR1	NM_002222.7	c.6865C>T	p.Leu2289Leu	synonymous_variant	50/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7054C>T	p.Leu2352Leu	synonymous_variant	54/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7030C>T	p.Leu2344Leu	synonymous_variant	54/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7027C>T	p.Leu2343Leu	synonymous_variant	54/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7012C>T	p.Leu2338Leu	synonymous_variant	53/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7009C>T	p.Leu2337Leu	synonymous_variant	53/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6982C>T	p.Leu2328Leu	synonymous_variant	51/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6910C>T	p.Leu2304Leu	synonymous_variant	51/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6865C>T	p.Leu2289Leu	synonymous_variant	50/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4816C>T	p.Leu1606Leu	synonymous_variant	34/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4231C>T	p.Leu1411Leu	synonymous_variant	31/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3994C>T	p.Leu1332Leu	synonymous_variant	31/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37797 AN: 152088 Hom.: 5099 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.273

GnomAD3 exomes AF: 0.293 AC: 73061 AN: 249164 Hom.: 11290 AF XY: 0.292 AC XY: 39537 AN XY: 135192

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.289

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.286 AC: 418458 AN: 1461322 Hom.: 61376 Cov.: 35 AF XY: 0.286 AC XY: 208252 AN XY: 726968

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.405

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.249 AC: 37856 AN: 152206 Hom.: 5109 Cov.: 32 AF XY: 0.249 AC XY: 18493 AN XY: 74402

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.325

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.278

Alfa AF: 0.274 Hom.: 9962

Bravo AF: 0.252

Asia WGS AF: 0.306 AC: 1068 AN: 3478

EpiCase AF: 0.294

EpiControl AF: 0.293

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 04, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

Gillespie syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Spinocerebellar ataxia type 29 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.45
DANN	Benign	0.57

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: rs2291862; hg19: chr3-4842231; COSMIC: COSV56973948;