3-4753227-G-A

Variant names:

• chr3-4753227-G-A
• rs746039
• NM_001378452.1:c.5545-13303G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378452.1(ITPR1):​c.5545-13303G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,918 control chromosomes in the GnomAD database, including 51,915 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.83 (51915 hom., cov: 29)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.522
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5545-13303G>A		intron_variant	Intron 44 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5500-13303G>A		intron_variant	Intron 43 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.5401-13303G>A		intron_variant	Intron 41 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.5356-13303G>A		intron_variant	Intron 40 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5545-13303G>A		intron_variant	Intron 44 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5521-13303G>A		intron_variant	Intron 44 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5518-13303G>A		intron_variant	Intron 44 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5503-13303G>A		intron_variant	Intron 43 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5500-13303G>A		intron_variant	Intron 43 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5473-13303G>A		intron_variant	Intron 41 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5401-13303G>A		intron_variant	Intron 41 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5356-13303G>A		intron_variant	Intron 40 of 57	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3307-13303G>A		intron_variant	Intron 24 of 41			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2845-13303G>A		intron_variant	Intron 22 of 38			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2452-13303G>A		intron_variant	Intron 20 of 38			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125335 AN: 151800 Hom.: 51872 Cov.: 29

Gnomad AFR AF: 0.872

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.837

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.830

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.823

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.826 AC: 125433 AN: 151918 Hom.: 51915 Cov.: 29 AF XY: 0.829 AC XY: 61532 AN XY: 74254

African (AFR) AF: 0.872 AC: 36127 AN: 41416

American (AMR) AF: 0.837 AC: 12786 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2869 AN: 3470

East Asian (EAS) AF: 0.994 AC: 5101 AN: 5130

South Asian (SAS) AF: 0.829 AC: 3991 AN: 4812

European-Finnish (FIN) AF: 0.816 AC: 8611 AN: 10556

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53215 AN: 67942

Other (OTH) AF: 0.821 AC: 1735 AN: 2112

Alfa AF: 0.798 Hom.: 104116

Bravo AF: 0.832

Asia WGS AF: 0.892 AC: 3105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.079
DANN	Benign	0.71
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746039; hg19: chr3-4794911;