chr3-4640545-G-A

Variant names:

• chr3-4640545-G-A
• rs4073665
• NM_001378452.1:c.366+1075G>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.366+1075G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 152,202 control chromosomes in the GnomAD database, including 53,396 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 0.84 (53396 hom., cov: 32)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• Publications: 5 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.366+1075G>A		intron_variant	Intron 6 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.366+1075G>A		intron_variant	Intron 6 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.366+1075G>A		intron_variant	Intron 6 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.366+1075G>A		intron_variant	Intron 6 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.366+1075G>A		intron_variant	Intron 6 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.366+1075G>A		intron_variant	Intron 6 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.366+1075G>A		intron_variant	Intron 6 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.366+1075G>A		intron_variant	Intron 6 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.366+1075G>A		intron_variant	Intron 6 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.366+1075G>A		intron_variant	Intron 4 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.366+1075G>A		intron_variant	Intron 6 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.366+1075G>A		intron_variant	Intron 6 of 57	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.835 AC: 127063 AN: 152084 Hom.: 53376 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.871

Gnomad OTH AF: 0.833

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

GnomAD4 genome AF: 0.835 AC: 127136 AN: 152202 Hom.: 53396 Cov.: 32 AF XY: 0.838 AC XY: 62357 AN XY: 74428

African (AFR) AF: 0.751 AC: 31160 AN: 41494

American (AMR) AF: 0.841 AC: 12870 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2897 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4370 AN: 5178

South Asian (SAS) AF: 0.884 AC: 4260 AN: 4818

European-Finnish (FIN) AF: 0.915 AC: 9707 AN: 10608

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.871 AC: 59222 AN: 68024

Other (OTH) AF: 0.835 AC: 1760 AN: 2108

Alfa AF: 0.855 Hom.: 104939

Bravo AF: 0.826

Asia WGS AF: 0.853 AC: 2966 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.44
DANN	Benign	0.25
PhyloP100		0.28
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: rs4073665; hg19: chr3-4682229;