rs901854

chr3-4814550-G-Achr3-4814550-G-Cchr3-4814550-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):c.7689G>A(p.Lys2563=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,590,260 control chromosomes in the GnomAD database, including 291,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (26468 hom., cov: 24)
  • Exomes 𝑓: 0.61 (265457 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.44

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-4814550-G-A is Benign according to our data. Variant chr3-4814550-G-A is described in ClinVar as [Benign]. Clinvar id is 129304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4814550-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.7689G>A	p.Lys2563=	synonymous_variant	58/62	ENST00000649015.2
LOC124906209	XR_007095795.1	n.725-119C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.7689G>A	p.Lys2563=	synonymous_variant	58/62		NM_001378452.1
	ENST00000693140.1	n.581+11196C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.595 AC: 88686 AN: 148982 Hom.: 26453 Cov.: 24

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.599

GnomAD3 exomes AF: 0.604 AC: 149857 AN: 248248 Hom.: 45734 AF XY: 0.605 AC XY: 81516 AN XY: 134688

Gnomad AFR exome AF: 0.556

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.738

Gnomad SAS exome AF: 0.586

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.608 AC: 876888 AN: 1441170 Hom.: 265457 Cov.: 36 AF XY: 0.609 AC XY: 436309 AN XY: 716730

Gnomad4 AFR exome AF: 0.568

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.605

Gnomad4 EAS exome AF: 0.722

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.653

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.595 AC: 88729 AN: 149090 Hom.: 26468 Cov.: 24 AF XY: 0.594 AC XY: 43117 AN XY: 72560

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.549

Gnomad4 ASJ AF: 0.592

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.592

Alfa AF: 0.602 Hom.: 43500

Bravo AF: 0.591

Asia WGS AF: 0.591 AC: 2056 AN: 3478

EpiCase AF: 0.601

EpiControl AF: 0.614

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -
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	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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 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. -

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	-0.45
Cadd	Benign	9.7
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs901854; hg19: chr3-4856234; COSMIC: COSV56999806; COSMIC: COSV56999806;