3-4520983-T-G

Variant names:

• chr3-4520983-T-G
• rs1038639
• NM_001378452.1:c.93-41T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.93-41T>G variant causes a intron change. The variant allele was found at a frequency of 0.553 in 1,475,666 control chromosomes in the GnomAD database, including 235,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18726 hom., cov: 32)
  • Exomes 𝑓: 0.56 (216691 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.22
• Publications: 19 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 3-4520983-T-G is Benign according to our data. Variant chr3-4520983-T-G is described in ClinVar as Benign. ClinVar VariationId is 1293507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.713 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.93-41T>G		intron	N/A	NP_001365381.1
	ITPR1	NM_001168272.2		c.93-41T>G		intron	N/A	NP_001161744.1
	ITPR1	NM_001099952.4		c.93-41T>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.93-41T>G		intron	N/A	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.93-41T>G		intron	N/A	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.93-41T>G		intron	N/A	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68817 AN: 152000 Hom.: 18719 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.514

GnomAD2 exomes AF: 0.558 AC: 136815 AN: 245052 AF XY: 0.576

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.647

Gnomad EAS exome AF: 0.723

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.584

GnomAD4 exome AF: 0.564 AC: 746697 AN: 1323548 Hom.: 216691 Cov.: 19 AF XY: 0.572 AC XY: 380895 AN XY: 666058

African (AFR) AF: 0.120 AC: 3720 AN: 30962

American (AMR) AF: 0.478 AC: 21089 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16160 AN: 25166

East Asian (EAS) AF: 0.675 AC: 26247 AN: 38908

South Asian (SAS) AF: 0.720 AC: 59965 AN: 83286

European-Finnish (FIN) AF: 0.499 AC: 26538 AN: 53144

Middle Eastern (MID) AF: 0.672 AC: 3695 AN: 5500

European-Non Finnish (NFE) AF: 0.565 AC: 557909 AN: 986732

Other (OTH) AF: 0.563 AC: 31374 AN: 55722

GnomAD4 genome AF: 0.452 AC: 68824 AN: 152118 Hom.: 18726 Cov.: 32 AF XY: 0.458 AC XY: 34041 AN XY: 74362

African (AFR) AF: 0.137 AC: 5673 AN: 41504

American (AMR) AF: 0.513 AC: 7852 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2258 AN: 3470

East Asian (EAS) AF: 0.720 AC: 3720 AN: 5168

South Asian (SAS) AF: 0.734 AC: 3537 AN: 4822

European-Finnish (FIN) AF: 0.492 AC: 5202 AN: 10568

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.571 AC: 38809 AN: 67976

Other (OTH) AF: 0.516 AC: 1090 AN: 2114

Alfa AF: 0.539 Hom.: 82125

Bravo AF: 0.434

Asia WGS AF: 0.685 AC: 2380 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.42
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		4.2
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: rs1038639; hg19: chr3-4562667; COSMIC: COSV107311158;