chr3-4516557-G-A

Position:

chr3-4516557-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001378452.1(ITPR1):c.66G>A(p.Ser22Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,603,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 2 hom. )

Consequence

ITPR1
NM_001378452.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0170

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 3-4516557-G-A is Benign according to our data. Variant chr3-4516557-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 345339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.017 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000447 (68/152154) while in subpopulation NFE AF= 0.00075 (51/68008). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/61		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/59		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/58		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/62		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/62	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/62			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/61			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/61	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.66G>A	p.Ser22Ser	synonymous_variant	1/59			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/59	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.66G>A	p.Ser22Ser	synonymous_variant	3/58	1		ENSP00000397885.2	Q14643-4

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000442

AC:

107

AN:

242082

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

131640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000172

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000839

Gnomad NFE exome

AF:

0.000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000543

AC:

788

AN:

1451404

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

371

AN XY:

721994

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.000300

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000767

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000600

Gnomad4 NFE exome

AF:

0.000650

Gnomad4 OTH exome

AF:

0.000317

GnomAD4 genome

AF:

0.000447

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000552

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000600

Hom.:

Bravo

AF:

0.000382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ITPR1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2024

- -

ITPR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.8

DANN

Benign

0.83

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

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