rs375801584

Variant names:

• chr3-4673211-G-T
• rs375801584
• NM_001378452.1:c.2280G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001378452.1(ITPR1):​c.2280G>T​(p.Leu760Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000125 in 1,613,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.73
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 3-4673211-G-T is Benign according to our data. Variant chr3-4673211-G-T is described in ClinVar as [Benign]. Clinvar id is 345711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000138 (21/152286) while in subpopulation EAS AF = 0.00386 (20/5176). AF 95% confidence interval is 0.00256. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 20 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 20 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 20 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 20 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 18 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2280G>T	p.Leu760Leu	synonymous_variant	Exon 21 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2235G>T	p.Leu745Leu	synonymous_variant	Exon 20 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.117G>T	p.Leu39Leu	synonymous_variant	Exon 2 of 42			ENSP00000497872.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000430 AC: 107 AN: 249070 AF XY: 0.000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00597

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461672 Hom.: 1 Cov.: 31 AF XY: 0.000120 AC XY: 87 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00383 AC: 152 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111842

Other (OTH) AF: 0.000414 AC: 25 AN: 60374

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000193

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 22, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.9
DANN	Benign	0.48
PhyloP100		5.7
Mutation Taster		=81/19	polymorphism

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: rs375801584; hg19: chr3-4714895;