rs41289628

Variant names:

• chr3-4663132-G-A
• rs41289628
• NM_001378452.1:c.1480G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.1480G>A​(p.Val494Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,613,778 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (28 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 8.10
• 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: 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 (MetaRNN=0.009360462).
• BP6: Variant 3-4663132-G-A is Benign according to our data. Variant chr3-4663132-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0041 (624/152272) while in subpopulation SAS AF = 0.00768 (37/4820). AF 95% confidence interval is 0.00572. There are 5 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1480G>A	p.Val494Ile	missense	Exon 16 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.1435G>A	p.Val479Ile	missense	Exon 15 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.1480G>A	p.Val494Ile	missense	Exon 16 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.1480G>A	p.Val494Ile	missense	Exon 16 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.1480G>A	p.Val494Ile	missense	Exon 16 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.1480G>A	p.Val494Ile	missense	Exon 16 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152154 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00461 AC: 1148 AN: 249094 AF XY: 0.00504

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00186

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00498 AC: 7280 AN: 1461506 Hom.: 28 Cov.: 30 AF XY: 0.00512 AC XY: 3721 AN XY: 727044

African (AFR) AF: 0.000687 AC: 23 AN: 33472

American (AMR) AF: 0.00277 AC: 124 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00961 AC: 251 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00686 AC: 592 AN: 86238

European-Finnish (FIN) AF: 0.00217 AC: 116 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00525 AC: 5832 AN: 1111706

Other (OTH) AF: 0.00500 AC: 302 AN: 60364

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152272 Hom.: 5 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74466

African (AFR) AF: 0.000842 AC: 35 AN: 41550

American (AMR) AF: 0.00405 AC: 62 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00768 AC: 37 AN: 4820

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00620 AC: 422 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00557 Hom.: 13

Bravo AF: 0.00386

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00203 AC: 8

ESP6500EA AF: 0.00649 AC: 54

ExAC AF: 0.00486 AC: 588

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00671

EpiControl AF: 0.00723

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	0.75	N
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.89	N
REVEL	Uncertain	0.37
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.19
MVP		0.71
MPC		0.60
ClinPred		0.014	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.36
Mutation Taster		=72/28	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

Other links and lift over

dbSNP: rs41289628; hg19: chr3-4704816; COSMIC: COSV56991440;