chr3-4675127-A-C

Variant names:

• chr3-4675127-A-C
• rs2306877
• NM_001378452.1:c.2658A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.2658A>C​(p.Leu886Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,605,562 control chromosomes in the GnomAD database, including 43,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5980 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37154 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.52
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-4675127-A-C is Benign according to our data. Variant chr3-4675127-A-C is described in ClinVar as Benign. ClinVar VariationId is 129299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 22 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 22 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 22 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 22 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 20 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2658A>C	p.Leu886Leu	synonymous_variant	Exon 23 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2613A>C	p.Leu871Leu	synonymous_variant	Exon 22 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.495A>C	p.Leu165Leu	synonymous_variant	Exon 4 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.-16A>C		upstream_gene_variant				ENSP00000498149.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40967 AN: 151992 Hom.: 5968 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.271 AC: 67189 AN: 247978 AF XY: 0.266

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.214 AC: 310432 AN: 1453452 Hom.: 37154 Cov.: 29 AF XY: 0.217 AC XY: 157259 AN XY: 723564

African (AFR) AF: 0.374 AC: 12441 AN: 33266

American (AMR) AF: 0.402 AC: 17897 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3932 AN: 26086

East Asian (EAS) AF: 0.290 AC: 11463 AN: 39592

South Asian (SAS) AF: 0.376 AC: 32303 AN: 85830

European-Finnish (FIN) AF: 0.294 AC: 15675 AN: 53356

Middle Eastern (MID) AF: 0.182 AC: 1047 AN: 5756

European-Non Finnish (NFE) AF: 0.183 AC: 202618 AN: 1104988

Other (OTH) AF: 0.217 AC: 13056 AN: 60088

GnomAD4 genome AF: 0.270 AC: 41031 AN: 152110 Hom.: 5980 Cov.: 32 AF XY: 0.276 AC XY: 20548 AN XY: 74344

African (AFR) AF: 0.366 AC: 15172 AN: 41460

American (AMR) AF: 0.330 AC: 5046 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1502 AN: 5178

South Asian (SAS) AF: 0.402 AC: 1938 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3136 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13016 AN: 67990

Other (OTH) AF: 0.242 AC: 512 AN: 2114

Alfa AF: 0.212 Hom.: 7630

Bravo AF: 0.272

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Gillespie syndrome Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 29 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Spinocerebellar ataxia type 15/16 Benign:1

Aug 19, 2021

Genome-Nilou Lab

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	-0.88
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		-1.5
PromoterAI		0.025	Neutral
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2306877; hg19: chr3-4716811; COSMIC: COSV56983696; COSMIC: COSV56983696;