rs182840163

Variant names:

• chr3-4691209-C-T
• rs182840163
• NM_001378452.1:c.3894C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.3894C>T​(p.Asn1298Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,613,126 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0220
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 3-4691209-C-T is Benign according to our data. Variant chr3-4691209-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 289460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.022 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0022 (335/152238) while in subpopulation AFR AF = 0.0077 (320/41558). AF 95% confidence interval is 0.00701. There are 1 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.3894C>T	p.Asn1298Asn	synonymous_variant	Exon 32 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3849C>T	p.Asn1283Asn	synonymous_variant	Exon 31 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3867C>T	p.Asn1289Asn	synonymous_variant	Exon 32 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3822C>T	p.Asn1274Asn	synonymous_variant	Exon 31 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3894C>T	p.Asn1298Asn	synonymous_variant	Exon 32 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3867C>T	p.Asn1289Asn	synonymous_variant	Exon 32 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3867C>T	p.Asn1289Asn	synonymous_variant	Exon 32 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3849C>T	p.Asn1283Asn	synonymous_variant	Exon 31 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3849C>T	p.Asn1283Asn	synonymous_variant	Exon 31 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3822C>T	p.Asn1274Asn	synonymous_variant	Exon 29 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3867C>T	p.Asn1289Asn	synonymous_variant	Exon 32 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3822C>T	p.Asn1274Asn	synonymous_variant	Exon 31 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1704C>T	p.Asn568Asn	synonymous_variant	Exon 13 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1194C>T	p.Asn398Asn	synonymous_variant	Exon 10 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.801C>T	p.Asn267Asn	synonymous_variant	Exon 8 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.000531 AC: 132 AN: 248364 AF XY: 0.000379

Gnomad AFR exome AF: 0.00775

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1460888 Hom.: 2 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 726660

African (AFR) AF: 0.00816 AC: 273 AN: 33456

American (AMR) AF: 0.000336 AC: 15 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111400

Other (OTH) AF: 0.000364 AC: 22 AN: 60358

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74432

African (AFR) AF: 0.00770 AC: 320 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00256

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: BP4, BP7 -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 10, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		-0.022
Mutation Taster		=99/1	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs182840163; hg19: chr3-4732893;