rs711631

Variant names:

• chr3-4814496-T-C
• rs711631
• NM_001378452.1:c.7635T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-4814496-T-C
• chr3-4814496-T-A

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.7635T>C​(p.Thr2545Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,613,016 control chromosomes in the GnomAD database, including 554,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49235 hom., cov: 29)
  • Exomes 𝑓: 0.83 (504868 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.33
• Publications: 24 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-4814496-T-C is Benign according to our data. Variant chr3-4814496-T-C is described in ClinVar as Benign. ClinVar VariationId is 129303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 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.7635T>C	p.Thr2545Thr	synonymous	Exon 58 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.7590T>C	p.Thr2530Thr	synonymous	Exon 57 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.7491T>C	p.Thr2497Thr	synonymous	Exon 55 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.7635T>C	p.Thr2545Thr	synonymous	Exon 58 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.7611T>C	p.Thr2537Thr	synonymous	Exon 58 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.7608T>C	p.Thr2536Thr	synonymous	Exon 58 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.802 AC: 121641 AN: 151684 Hom.: 49209 Cov.: 29

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.962

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.829 AC: 206711 AN: 249264 AF XY: 0.824

Gnomad AFR exome AF: 0.696

Gnomad AMR exome AF: 0.843

Gnomad ASJ exome AF: 0.807

Gnomad EAS exome AF: 0.968

Gnomad FIN exome AF: 0.912

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.830 AC: 1212796 AN: 1461214 Hom.: 504868 Cov.: 44 AF XY: 0.827 AC XY: 601450 AN XY: 726908

African (AFR) AF: 0.697 AC: 23346 AN: 33472

American (AMR) AF: 0.838 AC: 37464 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 21106 AN: 26132

East Asian (EAS) AF: 0.936 AC: 37162 AN: 39694

South Asian (SAS) AF: 0.745 AC: 64261 AN: 86238

European-Finnish (FIN) AF: 0.909 AC: 48523 AN: 53394

Middle Eastern (MID) AF: 0.739 AC: 4256 AN: 5762

European-Non Finnish (NFE) AF: 0.834 AC: 927270 AN: 1111448

Other (OTH) AF: 0.819 AC: 49408 AN: 60350

GnomAD4 genome AF: 0.802 AC: 121715 AN: 151802 Hom.: 49235 Cov.: 29 AF XY: 0.805 AC XY: 59730 AN XY: 74194

African (AFR) AF: 0.708 AC: 29246 AN: 41328

American (AMR) AF: 0.802 AC: 12243 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2780 AN: 3464

East Asian (EAS) AF: 0.962 AC: 4929 AN: 5124

South Asian (SAS) AF: 0.736 AC: 3543 AN: 4812

European-Finnish (FIN) AF: 0.923 AC: 9743 AN: 10552

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.833 AC: 56625 AN: 67954

Other (OTH) AF: 0.765 AC: 1612 AN: 2108

Alfa AF: 0.817 Hom.: 99953

Bravo AF: 0.795

Asia WGS AF: 0.802 AC: 2790 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Gillespie syndrome (1)
-	-	1	Spinocerebellar ataxia type 15/16 (1)
-	-	1	Spinocerebellar ataxia type 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.49
DANN	Benign	0.67
PhyloP100		-1.3
PromoterAI		-0.072	Neutral
Mutation Taster		=97/3	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: rs711631; hg19: chr3-4856180; COSMIC: COSV56998224; COSMIC: COSV56998224;