NM_001378452.1:c.7701+3A>G

Variant names:

• chr3-4814565-A-G
• rs533303665
• NM_001378452.1:c.7701+3A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.7701+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,599,166 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00041 (8 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.6670
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.46

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]

ENSG00000235978 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-4814565-A-G is Benign according to our data. Variant chr3-4814565-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 586056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000185 (28/151660) while in subpopulation SAS AF= 0.00544 (26/4780). AF 95% confidence interval is 0.00381. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7701+3A>G		splice_region_variant, intron_variant	Intron 58 of 61	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7701+3A>G		splice_region_variant, intron_variant	Intron 58 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7677+3A>G		splice_region_variant, intron_variant	Intron 58 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7674+3A>G		splice_region_variant, intron_variant	Intron 58 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7659+3A>G		splice_region_variant, intron_variant	Intron 57 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7656+3A>G		splice_region_variant, intron_variant	Intron 57 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7629+3A>G		splice_region_variant, intron_variant	Intron 55 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7557+3A>G		splice_region_variant, intron_variant	Intron 55 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7512+3A>G		splice_region_variant, intron_variant	Intron 54 of 57	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5463+3A>G		splice_region_variant, intron_variant	Intron 38 of 41			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4878+3A>G		splice_region_variant, intron_variant	Intron 35 of 38			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4641+3A>G		splice_region_variant, intron_variant	Intron 35 of 38			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151542 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00543

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000839 AC: 208 AN: 248032 Hom.: 4 AF XY: 0.00105 AC XY: 141 AN XY: 134632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00665

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.000406 AC: 588 AN: 1447506 Hom.: 8 Cov.: 31 AF XY: 0.000573 AC XY: 412 AN XY: 718484

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000453

GnomAD4 genome AF: 0.000185 AC: 28 AN: 151660 Hom.: 0 Cov.: 28 AF XY: 0.000243 AC XY: 18 AN XY: 74100

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00544

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000453

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ITPR1-related disorder Benign:1

Apr 23, 2024

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). -

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	-0.61
CADD	Benign	17
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.64
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: rs533303665; hg19: chr3-4856249;