rs61757108

Variant names:

• chr3-4691236-C-T
• rs61757108
• NM_001378452.1:c.3921C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001378452.1(ITPR1):​c.3921C>T​(p.His1307His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,612,902 control chromosomes in the GnomAD database, including 1 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 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.73

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 3-4691236-C-T is Benign according to our data. Variant chr3-4691236-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284759.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=2.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000322 (49/152322) while in subpopulation SAS AF= 0.00083 (4/4822). AF 95% confidence interval is 0.00038. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.3921C>T	p.His1307His	synonymous_variant	Exon 32 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3876C>T	p.His1292His	synonymous_variant	Exon 31 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3894C>T	p.His1298His	synonymous_variant	Exon 32 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3849C>T	p.His1283His	synonymous_variant	Exon 31 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3921C>T	p.His1307His	synonymous_variant	Exon 32 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3894C>T	p.His1298His	synonymous_variant	Exon 32 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3894C>T	p.His1298His	synonymous_variant	Exon 32 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3876C>T	p.His1292His	synonymous_variant	Exon 31 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3876C>T	p.His1292His	synonymous_variant	Exon 31 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3849C>T	p.His1283His	synonymous_variant	Exon 29 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3894C>T	p.His1298His	synonymous_variant	Exon 32 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3849C>T	p.His1283His	synonymous_variant	Exon 31 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1731C>T	p.His577His	synonymous_variant	Exon 13 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1221C>T	p.His407His	synonymous_variant	Exon 10 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.828C>T	p.His276His	synonymous_variant	Exon 8 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000270 AC: 67 AN: 248546 Hom.: 1 AF XY: 0.000245 AC XY: 33 AN XY: 134818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000444

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000390 AC: 569 AN: 1460580 Hom.: 1 Cov.: 30 AF XY: 0.000366 AC XY: 266 AN XY: 726562

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000474

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000332

EpiCase AF: 0.000545

EpiControl AF: 0.000536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: BP4, BP7 -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 07, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ITPR1-related disorder Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.6
DANN	Benign	0.64

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

Other links and lift over

dbSNP: rs61757108; hg19: chr3-4732920;