3-4683555-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001378452.1(ITPR1):c.3327+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,406 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITPR1
NM_001378452.1 splice_region, intron

Scores

Splicing: ADA: 0.00002082

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.204

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.3327+4G>T	splice_region_variant, intron_variant	Intron 27 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.3282+4G>T	splice_region_variant, intron_variant	Intron 26 of 60		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.3300+4G>T	splice_region_variant, intron_variant	Intron 27 of 58		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.3255+4G>T	splice_region_variant, intron_variant	Intron 26 of 57		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.3327+4G>T	splice_region_variant, intron_variant	Intron 27 of 61		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.3300+4G>T	splice_region_variant, intron_variant	Intron 27 of 61	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.3300+4G>T	splice_region_variant, intron_variant	Intron 27 of 61			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.3282+4G>T	splice_region_variant, intron_variant	Intron 26 of 60			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.3282+4G>T	splice_region_variant, intron_variant	Intron 26 of 60	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.3255+4G>T	splice_region_variant, intron_variant	Intron 24 of 58			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.3300+4G>T	splice_region_variant, intron_variant	Intron 27 of 58	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.3255+4G>T	splice_region_variant, intron_variant	Intron 26 of 57	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.1137+4G>T	splice_region_variant, intron_variant	Intron 8 of 41			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.627+4G>T	splice_region_variant, intron_variant	Intron 5 of 38			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.234+4G>T	splice_region_variant, intron_variant	Intron 3 of 38			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726912

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111606

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 26 of the ITPR1 gene. It does not directly change the encoded amino acid sequence of the ITPR1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1966498). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.29

PhyloP100

-0.20

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0040

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over