chr3-4788048-A-G

Variant names:

• chr3-4788048-A-G
• rs13079522
• NM_001378452.1:c.6717A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.6717A>G​(p.Thr2239Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,611,078 control chromosomes in the GnomAD database, including 82,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7349 hom., cov: 32)
  • Exomes 𝑓: 0.32 (75464 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.89
• Publications: 21 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 3-4788048-A-G is Benign according to our data. Variant chr3-4788048-A-G is described in ClinVar as Benign. ClinVar VariationId is 129301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 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.6717A>G	p.Thr2239Thr	synonymous	Exon 52 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.6672A>G	p.Thr2224Thr	synonymous	Exon 51 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.6573A>G	p.Thr2191Thr	synonymous	Exon 49 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.6717A>G	p.Thr2239Thr	synonymous	Exon 52 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.6693A>G	p.Thr2231Thr	synonymous	Exon 52 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.6690A>G	p.Thr2230Thr	synonymous	Exon 52 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46399 AN: 151972 Hom.: 7342 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.301 AC: 73830 AN: 245388 AF XY: 0.307

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.0941

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.328

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.318 AC: 463693 AN: 1458988 Hom.: 75464 Cov.: 32 AF XY: 0.319 AC XY: 231461 AN XY: 725554

African (AFR) AF: 0.268 AC: 8954 AN: 33446

American (AMR) AF: 0.240 AC: 10662 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 8193 AN: 26074

East Asian (EAS) AF: 0.102 AC: 4057 AN: 39658

South Asian (SAS) AF: 0.336 AC: 28831 AN: 85726

European-Finnish (FIN) AF: 0.395 AC: 21034 AN: 53302

Middle Eastern (MID) AF: 0.282 AC: 1625 AN: 5766

European-Non Finnish (NFE) AF: 0.326 AC: 361885 AN: 1110280

Other (OTH) AF: 0.306 AC: 18452 AN: 60308

GnomAD4 genome AF: 0.305 AC: 46427 AN: 152090 Hom.: 7349 Cov.: 32 AF XY: 0.307 AC XY: 22854 AN XY: 74334

African (AFR) AF: 0.272 AC: 11281 AN: 41498

American (AMR) AF: 0.247 AC: 3779 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3468

East Asian (EAS) AF: 0.104 AC: 537 AN: 5168

South Asian (SAS) AF: 0.340 AC: 1636 AN: 4814

European-Finnish (FIN) AF: 0.408 AC: 4314 AN: 10574

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22649 AN: 67966

Other (OTH) AF: 0.274 AC: 580 AN: 2114

Alfa AF: 0.309 Hom.: 7187

Bravo AF: 0.290

Asia WGS AF: 0.213 AC: 738 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.54
DANN	Benign	0.45
PhyloP100		-1.9
Mutation Taster		=98/2	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: rs13079522; hg19: chr3-4829732; COSMIC: COSV57002458; COSMIC: COSV57002458;