3-4662253-C-T

Position:

• chr3-4662253-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.1412+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,582,676 control chromosomes in the GnomAD database, including 1,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (346 hom., cov: 32)
  • Exomes 𝑓: 0.022 (881 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0970

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-4662253-C-T is Benign according to our data. Variant chr3-4662253-C-T is described in ClinVar as [Benign]. Clinvar id is 345646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4662253-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1412+11C>T		intron_variant		ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1367+11C>T		intron_variant			NP_001161744.1
ITPR1	NM_001099952.4	c.1412+11C>T		intron_variant			NP_001093422.2
ITPR1	NM_002222.7	c.1367+11C>T		intron_variant			NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1412+11C>T		intron_variant			NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1412+11C>T		intron_variant		5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1412+11C>T		intron_variant				ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1367+11C>T		intron_variant				ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1367+11C>T		intron_variant		1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1367+11C>T		intron_variant				ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1412+11C>T		intron_variant		1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1367+11C>T		intron_variant		1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7611 AN: 152082 Hom.: 341 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0926

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0406

GnomAD3 exomes AF: 0.0403 AC: 9018 AN: 223626 Hom.: 376 AF XY: 0.0351 AC XY: 4240 AN XY: 120950

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.00886

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0218 AC: 31179 AN: 1430476 Hom.: 881 Cov.: 30 AF XY: 0.0210 AC XY: 14856 AN XY: 708932

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.00386

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.00839

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0502 AC: 7645 AN: 152200 Hom.: 346 Cov.: 32 AF XY: 0.0515 AC XY: 3830 AN XY: 74412

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0231 Hom.: 55

Bravo AF: 0.0566

Asia WGS AF: 0.0690 AC: 241 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.82
CADD	Benign	4.8
DANN	Benign	0.30

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: rs7632000; hg19: chr3-4703937; COSMIC: COSV57005772;