3-4662253-C-T

Variant names:

• chr3-4662253-C-T
• rs7632000
• NM_001378452.1:c.1412+11C>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.1412+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,582,676 control chromosomes in the GnomAD database, including 1,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (346 hom., cov: 32)
  • Exomes 𝑓: 0.022 (881 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0970
• Publications: 11 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=-0.82).
• BP6: Variant 3-4662253-C-T is Benign according to our data. Variant chr3-4662253-C-T is described in ClinVar as Benign. ClinVar VariationId is 345646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 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.1412+11C>T		intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.1367+11C>T		intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.1412+11C>T		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.1412+11C>T		intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.1412+11C>T		intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.1412+11C>T		intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.0500 AC: 7611 AN: 152082 Hom.: 341 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0926

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0403 AC: 9018 AN: 223626 AF XY: 0.0351

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00273

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0218 AC: 31179 AN: 1430476 Hom.: 881 Cov.: 30 AF XY: 0.0210 AC XY: 14856 AN XY: 708932

African (AFR) AF: 0.104 AC: 3408 AN: 32724

American (AMR) AF: 0.108 AC: 4499 AN: 41606

Ashkenazi Jewish (ASJ) AF: 0.00386 AC: 95 AN: 24608

East Asian (EAS) AF: 0.119 AC: 4634 AN: 39078

South Asian (SAS) AF: 0.00839 AC: 680 AN: 81046

European-Finnish (FIN) AF: 0.0193 AC: 1011 AN: 52352

Middle Eastern (MID) AF: 0.0138 AC: 74 AN: 5350

European-Non Finnish (NFE) AF: 0.0138 AC: 15154 AN: 1094670

Other (OTH) AF: 0.0275 AC: 1624 AN: 59042

GnomAD4 genome AF: 0.0502 AC: 7645 AN: 152200 Hom.: 346 Cov.: 32 AF XY: 0.0515 AC XY: 3830 AN XY: 74412

African (AFR) AF: 0.101 AC: 4194 AN: 41510

American (AMR) AF: 0.0932 AC: 1425 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.115 AC: 598 AN: 5178

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4822

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1004 AN: 68014

Other (OTH) AF: 0.0402 AC: 85 AN: 2116

Alfa AF: 0.0260 Hom.: 91

Bravo AF: 0.0566

Asia WGS AF: 0.0690 AC: 241 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.30
PhyloP100		0.097
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: rs7632000; hg19: chr3-4703937; COSMIC: COSV57005772;