3-4766606-T-G

Variant names:

• chr3-4766606-T-G
• rs143093165
• NM_001378452.1:c.5621T>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.5621T>G​(p.Val1874Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,754 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (21 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 2.59

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 -19 ACMG points.

• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0079301).
• BP6: Variant 3-4766606-T-G is Benign according to our data. Variant chr3-4766606-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 289396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00229 (348/152234) while in subpopulation SAS AF= 0.00851 (41/4820). AF 95% confidence interval is 0.00644. There are 0 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5621T>G	p.Val1874Gly	missense_variant	Exon 45 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5576T>G	p.Val1859Gly	missense_variant	Exon 44 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5477T>G	p.Val1826Gly	missense_variant	Exon 42 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5432T>G	p.Val1811Gly	missense_variant	Exon 41 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5621T>G	p.Val1874Gly	missense_variant	Exon 45 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5597T>G	p.Val1866Gly	missense_variant	Exon 45 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5594T>G	p.Val1865Gly	missense_variant	Exon 45 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5579T>G	p.Val1860Gly	missense_variant	Exon 44 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5576T>G	p.Val1859Gly	missense_variant	Exon 44 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5549T>G	p.Val1850Gly	missense_variant	Exon 42 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5477T>G	p.Val1826Gly	missense_variant	Exon 42 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5432T>G	p.Val1811Gly	missense_variant	Exon 41 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3383T>G	p.Val1128Gly	missense_variant	Exon 25 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2921T>G	p.Val974Gly	missense_variant	Exon 23 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2528T>G	p.Val843Gly	missense_variant	Exon 21 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00277 AC: 690 AN: 249180 Hom.: 3 AF XY: 0.00328 AC XY: 443 AN XY: 135186

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00706

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00329 AC: 4815 AN: 1461520 Hom.: 21 Cov.: 30 AF XY: 0.00345 AC XY: 2509 AN XY: 727034

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00761

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74432

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00272 Hom.: 1

Bravo AF: 0.00197

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00243 AC: 20

ExAC AF: 0.00276 AC: 334

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00451

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: BS2 -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Feb 07, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple sclerosis Pathogenic:1

Jun 10, 2024

Department of Molecular Biology and Genetics, Acibadem University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ITPR1-related disorder Benign:1

May 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.38	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.47	T;T;T;T;T;T;T;T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0079	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	.;.;.;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.62	N;N;.;N;.;.;.;.;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.38	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.36	T;T;.;T;.;.;.;.;T;.
Polyphen		0.078	.;.;.;.;.;.;B;.;.;.
Vest4		0.19
MVP		0.39
MPC		0.20
ClinPred		0.0053	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.32

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: rs143093165; hg19: chr3-4808290; COSMIC: COSV100234216; COSMIC: COSV100234216;