rs2306878

Variant names:

• chr3-4683555-G-A
• rs2306878
• NM_001378452.1:c.3327+4G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4683555-G-A
• chr3-4683555-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.3327+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 0.00583 in 1,613,760 control chromosomes in the GnomAD database, including 289 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (252 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.0002047
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.204
• 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-4683555-G-A is Benign according to our data. Variant chr3-4683555-G-A is described in ClinVar as Benign. ClinVar VariationId is 345724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.3327+4G>A		splice_region intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.3282+4G>A		splice_region intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.3300+4G>A		splice_region intron	N/A	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.3327+4G>A		splice_region intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.3300+4G>A		splice_region intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.3300+4G>A		splice_region intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1276 AN: 152236 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.0124 AC: 3083 AN: 248984 AF XY: 0.0113

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.0697

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00556 AC: 8131 AN: 1461406 Hom.: 252 Cov.: 32 AF XY: 0.00542 AC XY: 3937 AN XY: 726912

African (AFR) AF: 0.000269 AC: 9 AN: 33474

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00800 AC: 209 AN: 26132

East Asian (EAS) AF: 0.0854 AC: 3391 AN: 39690

South Asian (SAS) AF: 0.00172 AC: 148 AN: 86250

European-Finnish (FIN) AF: 0.0604 AC: 3223 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000682 AC: 758 AN: 1111606

Other (OTH) AF: 0.00611 AC: 369 AN: 60366

GnomAD4 genome AF: 0.00836 AC: 1274 AN: 152354 Hom.: 37 Cov.: 33 AF XY: 0.0116 AC XY: 863 AN XY: 74508

African (AFR) AF: 0.000553 AC: 23 AN: 41584

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.0675 AC: 350 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0681 AC: 723 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00179 AC: 122 AN: 68040

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00231 Hom.: 3

Bravo AF: 0.00390

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	16
DANN	Benign	0.27
PhyloP100		-0.20
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.030
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: rs2306878; hg19: chr3-4725239; COSMIC: COSV56973923;