rs2306875

Positions:

chr3-4670729-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001378452.1(ITPR1):c.2007G>A(p.Lys669=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.668 in 1,569,864 control chromosomes in the GnomAD database, including 354,237 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34961 hom., cov: 32)

Exomes 𝑓: 0.67 ( 319276 hom. )

Consequence

ITPR1
NM_001378452.1 splice_region, synonymous

Scores

Splicing: ADA: 0.5656

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.61

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 3-4670729-G-A is Benign according to our data. Variant chr3-4670729-G-A is described in ClinVar as [Benign]. Clinvar id is 129298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4670729-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ITPR1	NM_001378452.1 linkuse as main transcript	c.2007G>A	p.Lys669=	splice_region_variant, synonymous_variant	20/62	ENST00000649015.2
ITPR1	NM_001168272.2 linkuse as main transcript	c.1962G>A	p.Lys654=	splice_region_variant, synonymous_variant	19/61
ITPR1	NM_001099952.4 linkuse as main transcript	c.2007G>A	p.Lys669=	splice_region_variant, synonymous_variant	20/59
ITPR1	NM_002222.7 linkuse as main transcript	c.1962G>A	p.Lys654=	splice_region_variant, synonymous_variant	19/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2 linkuse as main transcript	c.2007G>A	p.Lys669=	splice_region_variant, synonymous_variant	20/62		NM_001378452.1		Q14643-1

Frequencies

GnomAD3 genomes

AF:

0.675

AC:

102489

AN:

151924

Hom.:

34924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.705

Gnomad AMR

AF:

0.701

Gnomad ASJ

AF:

0.610

Gnomad EAS

AF:

0.355

Gnomad SAS

AF:

0.637

Gnomad FIN

AF:

0.692

Gnomad MID

AF:

0.596

Gnomad NFE

AF:

0.684

Gnomad OTH

AF:

0.646

GnomAD3 exomes

AF:

0.648

AC:

129425

AN:

199708

Hom.:

42872

AF XY:

0.643

AC XY:

68623

AN XY:

106652

show subpopulations

Gnomad AFR exome

AF:

0.684

Gnomad AMR exome

AF:

0.716

Gnomad ASJ exome

AF:

0.600

Gnomad EAS exome

AF:

0.354

Gnomad SAS exome

AF:

0.638

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.669

Gnomad OTH exome

AF:

0.647

GnomAD4 exome

AF:

0.668

AC:

946701

AN:

1417822

Hom.:

319276

Cov.:

AF XY:

0.666

AC XY:

468217

AN XY:

702542

show subpopulations

Gnomad4 AFR exome

AF:

0.688

Gnomad4 AMR exome

AF:

0.711

Gnomad4 ASJ exome

AF:

0.601

Gnomad4 EAS exome

AF:

0.348

Gnomad4 SAS exome

AF:

0.640

Gnomad4 FIN exome

AF:

0.698

Gnomad4 NFE exome

AF:

0.680

Gnomad4 OTH exome

AF:

0.651

GnomAD4 genome

AF:

0.675

AC:

102584

AN:

152042

Hom.:

34961

Cov.:

AF XY:

0.673

AC XY:

49998

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.697

Gnomad4 AMR

AF:

0.701

Gnomad4 ASJ

AF:

0.610

Gnomad4 EAS

AF:

0.354

Gnomad4 SAS

AF:

0.637

Gnomad4 FIN

AF:

0.692

Gnomad4 NFE

AF:

0.684

Gnomad4 OTH

AF:

0.644

Alfa

AF:

0.667

Hom.:

66817

Bravo

AF:

0.671

Asia WGS

AF:

0.536

AC:

1864

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2019	- -

Spinocerebellar ataxia type 29

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Autosomal dominant cerebellar ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.57

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: 29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over