rs56378811

Variant names:

• chr3-4516331-A-G
• rs56378811
• NM_001378452.1:c.-16-145A>G

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.-16-145A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 524,368 control chromosomes in the GnomAD database, including 6,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1540 hom., cov: 33)
  • Exomes 𝑓: 0.16 (5331 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69
• Publications: 2 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=-0.78).
• BP6: Variant 3-4516331-A-G is Benign according to our data. Variant chr3-4516331-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 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.-16-145A>G		intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.-16-145A>G		intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.-16-145A>G		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.-16-145A>G		intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.-16-145A>G		intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.-16-145A>G		intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19268 AN: 152118 Hom.: 1540 Cov.: 33

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.155 AC: 57853 AN: 372132 Hom.: 5331 AF XY: 0.152 AC XY: 29697 AN XY: 194834

African (AFR) AF: 0.0321 AC: 271 AN: 8438

American (AMR) AF: 0.158 AC: 1450 AN: 9190

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 1234 AN: 12170

East Asian (EAS) AF: 0.00134 AC: 33 AN: 24636

South Asian (SAS) AF: 0.0869 AC: 2556 AN: 29426

European-Finnish (FIN) AF: 0.195 AC: 6100 AN: 31346

Middle Eastern (MID) AF: 0.111 AC: 204 AN: 1830

European-Non Finnish (NFE) AF: 0.183 AC: 42506 AN: 232380

Other (OTH) AF: 0.154 AC: 3499 AN: 22716

GnomAD4 genome AF: 0.127 AC: 19266 AN: 152236 Hom.: 1540 Cov.: 33 AF XY: 0.124 AC XY: 9195 AN XY: 74426

African (AFR) AF: 0.0325 AC: 1351 AN: 41554

American (AMR) AF: 0.136 AC: 2079 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5192

South Asian (SAS) AF: 0.0778 AC: 376 AN: 4830

European-Finnish (FIN) AF: 0.191 AC: 2021 AN: 10588

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12652 AN: 68002

Other (OTH) AF: 0.129 AC: 272 AN: 2110

Alfa AF: 0.167 Hom.: 1372

Bravo AF: 0.121

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.56
PhyloP100		1.7
PromoterAI		0.0098	Neutral
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: rs56378811; hg19: chr3-4558015;