NM_001378452.1:c.789C>T

Variant names:

• chr3-4645662-C-T
• rs369681244
• NM_001378452.1:c.789C>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.789C>T​(p.Phe263Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0150

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=-0.45).
• BP6: Variant 3-4645662-C-T is Benign according to our data. Variant chr3-4645662-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447603.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.015 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000151 (23/152282) while in subpopulation SAS AF= 0.000415 (2/4818). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.789C>T	p.Phe263Phe	synonymous_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000197 AC: 49 AN: 248338 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1461324 Hom.: 0 Cov.: 32 AF XY: 0.000164 AC XY: 119 AN XY: 726894

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74458

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Sep 15, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.8
DANN	Benign	0.69

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: rs369681244; hg19: chr3-4687346;