rs2306878

Positions:

• chr3-4683555-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.3327+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,613,760 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (252 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002047
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.204

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-4683555-G-A is Benign according to our data. Variant chr3-4683555-G-A is described in ClinVar as [Benign]. Clinvar id is 345724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.3327+4G>A		splice_donor_region_variant, intron_variant		ENST00000649015.2
ITPR1	NM_001099952.4	c.3300+4G>A		splice_donor_region_variant, intron_variant
ITPR1	NM_001168272.2	c.3282+4G>A		splice_donor_region_variant, intron_variant
ITPR1	NM_002222.7	c.3255+4G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.3327+4G>A		splice_donor_region_variant, intron_variant			NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1276 AN: 152236 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0124 AC: 3083 AN: 248984 Hom.: 96 AF XY: 0.0113 AC XY: 1520 AN XY: 135046

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.0697

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00556 AC: 8131 AN: 1461406 Hom.: 252 Cov.: 32 AF XY: 0.00542 AC XY: 3937 AN XY: 726912

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00800

Gnomad4 EAS exome AF: 0.0854

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.0604

Gnomad4 NFE exome AF: 0.000682

Gnomad4 OTH exome AF: 0.00611

GnomAD4 genome AF: 0.00836 AC: 1274 AN: 152354 Hom.: 37 Cov.: 33 AF XY: 0.0116 AC XY: 863 AN XY: 74508

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.0675

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0681

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00262 Hom.: 3

Bravo AF: 0.00390

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 02, 2016

- -

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	-0.84
CADD	Benign	16
DANN	Benign	0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.030
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: rs2306878; hg19: chr3-4725239; COSMIC: COSV56973923;