rs304041

Variant names:

• chr3-4511284-G-T
• rs304041
• NM_001378452.1:c.-16-5192G>T

Variant summary

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

The NM_001378452.1(ITPR1):​c.-16-5192G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 151,976 control chromosomes in the GnomAD database, including 32,913 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 0.66 (32913 hom., cov: 31)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.267
• Publications: 4 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 = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.-16-5192G>T		intron_variant	Intron 2 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.-16-5192G>T		intron_variant	Intron 2 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.-16-5192G>T		intron_variant	Intron 2 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.-16-5192G>T		intron_variant	Intron 2 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.-16-5192G>T		intron_variant	Intron 2 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.-16-5192G>T		intron_variant	Intron 2 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.-16-5192G>T		intron_variant	Intron 2 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.-16-5192G>T		intron_variant	Intron 2 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.-16-5192G>T		intron_variant	Intron 2 of 60	1		ENSP00000401671.2
ITPR1	ENST00000357086.10	c.-16-5192G>T		intron_variant	Intron 2 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.-16-5192G>T		intron_variant	Intron 2 of 57	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99549 AN: 151858 Hom.: 32887 Cov.: 31

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.640

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.669

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

GnomAD4 genome AF: 0.655 AC: 99620 AN: 151976 Hom.: 32913 Cov.: 31 AF XY: 0.660 AC XY: 49050 AN XY: 74292

African (AFR) AF: 0.701 AC: 29033 AN: 41430

American (AMR) AF: 0.598 AC: 9141 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2426 AN: 3470

East Asian (EAS) AF: 0.802 AC: 4133 AN: 5154

South Asian (SAS) AF: 0.783 AC: 3772 AN: 4816

European-Finnish (FIN) AF: 0.640 AC: 6752 AN: 10552

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42217 AN: 67956

Other (OTH) AF: 0.669 AC: 1407 AN: 2104

Alfa AF: 0.627 Hom.: 4734

Bravo AF: 0.649

Asia WGS AF: 0.789 AC: 2744 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	4.9
DANN	Benign	0.74
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs304041; hg19: chr3-4552968;