rs200705345

Positions:

• chr3-4680642-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001378452.1(ITPR1):​c.3057A>G​(p.Ser1019Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,613,926 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 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.17

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-4680642-A-G is Benign according to our data. Variant chr3-4680642-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 345720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4680642-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.17 with no splicing effect.
• 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	c.3057A>G	p.Ser1019Ser	synonymous_variant	25/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3012A>G	p.Ser1004Ser	synonymous_variant	24/61		NP_001161744.1
ITPR1	NM_001099952.4	c.3030A>G	p.Ser1010Ser	synonymous_variant	25/59		NP_001093422.2
ITPR1	NM_002222.7	c.2985A>G	p.Ser995Ser	synonymous_variant	24/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3057A>G	p.Ser1019Ser	synonymous_variant	25/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3030A>G	p.Ser1010Ser	synonymous_variant	25/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3030A>G	p.Ser1010Ser	synonymous_variant	25/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3012A>G	p.Ser1004Ser	synonymous_variant	24/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3012A>G	p.Ser1004Ser	synonymous_variant	24/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2985A>G	p.Ser995Ser	synonymous_variant	22/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3030A>G	p.Ser1010Ser	synonymous_variant	25/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2985A>G	p.Ser995Ser	synonymous_variant	24/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.867A>G	p.Ser289Ser	synonymous_variant	6/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.357A>G	p.Ser119Ser	synonymous_variant	3/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.-37A>G		upstream_gene_variant				ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000884 AC: 220 AN: 248986 Hom.: 1 AF XY: 0.000940 AC XY: 127 AN XY: 135068

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000816 AC: 1193 AN: 1461566 Hom.: 2 Cov.: 30 AF XY: 0.000857 AC XY: 623 AN XY: 727060

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00347

Gnomad4 NFE exome AF: 0.000839

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000939 AC XY: 70 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000468

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000890

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ITPR1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 05, 2024

- -

ITPR1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

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 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 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	-0.78
CADD	Benign	2.7
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200705345; hg19: chr3-4722326;