NM_001378452.1:c.4536+651A>G

Variant names:

• chr3-4700592-A-G
• rs6762644
• NM_001378452.1:c.4536+651A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001378452.1(ITPR1):​c.4536+651A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 151,998 control chromosomes in the GnomAD database, including 11,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (11381 hom., cov: 31)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.400
• Publications: 74 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-4700592-A-G is Benign according to our data. Variant chr3-4700592-A-G is described in ClinVar as Benign. ClinVar VariationId is 225778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.4536+651A>G		intron	N/A	NP_001365381.1
	ITPR1	NM_001168272.2		c.4491+651A>G		intron	N/A	NP_001161744.1
	ITPR1	NM_001099952.4		c.4509+651A>G		intron	N/A	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4536+651A>G		intron	N/A	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.4509+651A>G		intron	N/A	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.4509+651A>G		intron	N/A	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56875 AN: 151880 Hom.: 11367 Cov.: 31

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0815

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.375 AC: 56948 AN: 151998 Hom.: 11381 Cov.: 31 AF XY: 0.368 AC XY: 27381 AN XY: 74306

African (AFR) AF: 0.466 AC: 19307 AN: 41406

American (AMR) AF: 0.300 AC: 4583 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3470

East Asian (EAS) AF: 0.0817 AC: 424 AN: 5188

South Asian (SAS) AF: 0.114 AC: 548 AN: 4820

European-Finnish (FIN) AF: 0.389 AC: 4106 AN: 10550

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26166 AN: 67964

Other (OTH) AF: 0.315 AC: 665 AN: 2108

Alfa AF: 0.378 Hom.: 24352

Bravo AF: 0.370

Asia WGS AF: 0.137 AC: 479 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		0.40
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: rs6762644; hg19: chr3-4742276;