chr3-4710317-C-T

Position:

• chr3-4710317-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.4843-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,536,034 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001639
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• 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]

LOC124906210 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-4710317-C-T is Benign according to our data. Variant chr3-4710317-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 447591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4710317-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00112 (171/152316) while in subpopulation NFE AF= 0.00204 (139/68038). AF 95% confidence interval is 0.00177. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4843-8C>T		splice_region_variant, intron_variant		ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4843-8C>T		splice_region_variant, intron_variant			NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4816-8C>T		splice_region_variant, intron_variant		5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4816-8C>T		splice_region_variant, intron_variant				ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4798-8C>T		splice_region_variant, intron_variant				ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4798-8C>T		splice_region_variant, intron_variant		1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4771-8C>T		splice_region_variant, intron_variant				ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4816-8C>T		splice_region_variant, intron_variant		1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4771-8C>T		splice_region_variant, intron_variant		1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2653-8C>T		splice_region_variant, intron_variant				ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2143-8C>T		splice_region_variant, intron_variant				ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1750-8C>T		splice_region_variant, intron_variant				ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000871 AC: 148 AN: 169962 Hom.: 0 AF XY: 0.000821 AC XY: 74 AN XY: 90092

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000362

Gnomad FIN exome AF: 0.000173

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.00184 AC: 2540 AN: 1383718 Hom.: 7 Cov.: 30 AF XY: 0.00171 AC XY: 1160 AN XY: 679370

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.000785

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000321

Gnomad4 FIN exome AF: 0.000160

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74482

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ITPR1: BP4 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 05, 2021

- -

ITPR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

This variant is classified as likely 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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Intellectual disability Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs41304179; hg19: chr3-4752001;