NM_001378452.1:c.5621T>G

Variant names:

• chr3-4766606-T-G
• rs143093165
• NM_001378452.1:c.5621T>G

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.5621T>G​(p.Val1874Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,754 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1874A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (21 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:9
• Conservation: PhyloP100: 2.59
• Publications: 9 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 (MetaRNN=0.0079301).
• BP6: Variant 3-4766606-T-G is Benign according to our data. Variant chr3-4766606-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 289396.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 = 0.00229 (348/152234) while in subpopulation SAS AF = 0.00851 (41/4820). AF 95% confidence interval is 0.00644. There are 0 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.5621T>G	p.Val1874Gly	missense	Exon 45 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.5576T>G	p.Val1859Gly	missense	Exon 44 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.5477T>G	p.Val1826Gly	missense	Exon 42 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.5621T>G	p.Val1874Gly	missense	Exon 45 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.5597T>G	p.Val1866Gly	missense	Exon 45 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.5594T>G	p.Val1865Gly	missense	Exon 45 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00277 AC: 690 AN: 249180 AF XY: 0.00328

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00329 AC: 4815 AN: 1461520 Hom.: 21 Cov.: 30 AF XY: 0.00345 AC XY: 2509 AN XY: 727034

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.00152 AC: 68 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00761 AC: 656 AN: 86246

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53398

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5766

European-Non Finnish (NFE) AF: 0.00339 AC: 3771 AN: 1111722

Other (OTH) AF: 0.00353 AC: 213 AN: 60366

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74432

African (AFR) AF: 0.000771 AC: 32 AN: 41526

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00851 AC: 41 AN: 4820

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00256 Hom.: 1

Bravo AF: 0.00197

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00243 AC: 20

ExAC AF: 0.00276 AC: 334

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	ITPR1-related disorder (1)
1	-	-	Multiple sclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.32
Sift	Benign	0.38	T
Sift4G	Benign	0.36	T
Polyphen		0.078	B
Vest4		0.19
MVP		0.39
MPC		0.20
ClinPred		0.0053	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.32
Mutation Taster		=99/1	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: rs143093165; hg19: chr3-4808290; COSMIC: COSV100234216; COSMIC: COSV100234216;