rs41289636

Variant names:

• chr3-4673157-G-A
• rs41289636
• NM_001378452.1:c.2226G>A
• ITPR1 p.Ala742Ala

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.2226G>A​(p.Ala742Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,746 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (42 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.83
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen, Orphanet
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-4673157-G-A is Benign according to our data. Variant chr3-4673157-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00458 (697/152296) while in subpopulation AMR AF = 0.00719 (110/15296). AF 95% confidence interval is 0.00632. There are 3 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.2226G>A	p.Ala742Ala	synonymous	Exon 21 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.2181G>A	p.Ala727Ala	synonymous	Exon 20 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.2226G>A	p.Ala742Ala	synonymous	Exon 21 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.2226G>A	p.Ala742Ala	synonymous	Exon 21 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.2226G>A	p.Ala742Ala	synonymous	Exon 21 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.2226G>A	p.Ala742Ala	synonymous	Exon 21 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00683

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00443 AC: 1101 AN: 248464 AF XY: 0.00457

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00398

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00733

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00641 AC: 9372 AN: 1461450 Hom.: 42 Cov.: 31 AF XY: 0.00621 AC XY: 4517 AN XY: 726992

African (AFR) AF: 0.000986 AC: 33 AN: 33478

American (AMR) AF: 0.00458 AC: 205 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86232

European-Finnish (FIN) AF: 0.00199 AC: 106 AN: 53384

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00770 AC: 8556 AN: 1111690

Other (OTH) AF: 0.00515 AC: 311 AN: 60366

GnomAD4 genome AF: 0.00458 AC: 697 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74474

African (AFR) AF: 0.00154 AC: 64 AN: 41558

American (AMR) AF: 0.00719 AC: 110 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00684 AC: 465 AN: 68032

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00540 Hom.: 0

Bravo AF: 0.00541

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00797

EpiControl AF: 0.00884

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	ITPR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.4
DANN	Benign	0.79
PhyloP100		-1.8
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41289636;

hg19: chr3-4714841;