rs61757111

Variant names:

• chr3-4733132-C-T
• rs61757111
• NM_001378452.1:c.5265C>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: {Likely_benign=2, Benign=3, Uncertain_significance=1}. 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 rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5265C>T	p.Asn1755Asn	synonymous_variant	Exon 43 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5220C>T	p.Asn1740Asn	synonymous_variant	Exon 42 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5121C>T	p.Asn1707Asn	synonymous_variant	Exon 40 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5076C>T	p.Asn1692Asn	synonymous_variant	Exon 39 of 58		NP_002213.5

Ensembl

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

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: BP4, BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 31, 2020

Athena Diagnostics

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	-0.24
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;