rs61757111

Positions:

• chr3-4733132-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.5265C>T​(p.Asn1755Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,816 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (5 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.344

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 3-4733132-C-T is Benign according to our data. Variant chr3-4733132-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197067.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=3}. Variant chr3-4733132-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.344 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (319/152336) while in subpopulation NFE AF= 0.00357 (243/68034). AF 95% confidence interval is 0.0032. There are 2 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5265C>T	p.Asn1755Asn	synonymous_variant	43/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5220C>T	p.Asn1740Asn	synonymous_variant	42/61		NP_001161744.1
ITPR1	NM_001099952.4	c.5121C>T	p.Asn1707Asn	synonymous_variant	40/59		NP_001093422.2
ITPR1	NM_002222.7	c.5076C>T	p.Asn1692Asn	synonymous_variant	39/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5265C>T	p.Asn1755Asn	synonymous_variant	43/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5241C>T	p.Asn1747Asn	synonymous_variant	43/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5238C>T	p.Asn1746Asn	synonymous_variant	43/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5223C>T	p.Asn1741Asn	synonymous_variant	42/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5220C>T	p.Asn1740Asn	synonymous_variant	42/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5193C>T	p.Asn1731Asn	synonymous_variant	40/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5121C>T	p.Asn1707Asn	synonymous_variant	40/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5076C>T	p.Asn1692Asn	synonymous_variant	39/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3027C>T	p.Asn1009Asn	synonymous_variant	23/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2565C>T	p.Asn855Asn	synonymous_variant	21/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2172C>T	p.Asn724Asn	synonymous_variant	19/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00192 AC: 478 AN: 248698 Hom.: 0 AF XY: 0.00189 AC XY: 255 AN XY: 134938

Gnomad AFR exome AF: 0.000647

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.000725

Gnomad SAS exome AF: 0.000786

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00301 AC: 4400 AN: 1461480 Hom.: 5 Cov.: 31 AF XY: 0.00288 AC XY: 2094 AN XY: 727008

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.00359

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74478

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00262 Hom.: 1

Bravo AF: 0.00194

EpiCase AF: 0.00240

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ITPR1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 31, 2020

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61757111; hg19: chr3-4774816;