rs746724784

Variant names:

• chr3-4788143-G-A
• rs746724784
• NM_001378452.1:c.6808+4G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4788143-G-A
• chr3-4788143-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001378452.1(ITPR1):​c.6808+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,202 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.0007844
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.44

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6808+4G>A		splice_region_variant, intron_variant	Intron 52 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6763+4G>A		splice_region_variant, intron_variant	Intron 51 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.6664+4G>A		splice_region_variant, intron_variant	Intron 49 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.6619+4G>A		splice_region_variant, intron_variant	Intron 48 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6808+4G>A		splice_region_variant, intron_variant	Intron 52 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6784+4G>A		splice_region_variant, intron_variant	Intron 52 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6781+4G>A		splice_region_variant, intron_variant	Intron 52 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6766+4G>A		splice_region_variant, intron_variant	Intron 51 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6763+4G>A		splice_region_variant, intron_variant	Intron 51 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6736+4G>A		splice_region_variant, intron_variant	Intron 49 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6664+4G>A		splice_region_variant, intron_variant	Intron 49 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6619+4G>A		splice_region_variant, intron_variant	Intron 48 of 57	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4570+4G>A		splice_region_variant, intron_variant	Intron 32 of 41			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4108+4G>A		splice_region_variant, intron_variant	Intron 30 of 38			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3715+4G>A		splice_region_variant, intron_variant	Intron 28 of 38			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000922 AC: 2 AN: 216864 Hom.: 0 AF XY: 0.0000172 AC XY: 2 AN XY: 116108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000653

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1442016 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 8 AN XY: 715128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000479

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Oct 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 586053). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change falls in intron 48 of the ITPR1 gene. It does not directly change the encoded amino acid sequence of the ITPR1 protein, but it affects a nucleotide within the consensus splice site of the intron. -

May 29, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.086
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: rs746724784; hg19: chr3-4829827;