rs192863290

Variant names:

• chr3-4699878-C-G
• rs192863290
• NM_001378452.1:c.4473C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4699878-C-G
• chr3-4699878-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.4473C>G​(p.Ile1491Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1491I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.31
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13816819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4473C>G	p.Ile1491Met	missense_variant	Exon 35 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4428C>G	p.Ile1476Met	missense_variant	Exon 34 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.4446C>G	p.Ile1482Met	missense_variant	Exon 35 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.4401C>G	p.Ile1467Met	missense_variant	Exon 34 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4473C>G	p.Ile1491Met	missense_variant	Exon 35 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4446C>G	p.Ile1482Met	missense_variant	Exon 35 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4446C>G	p.Ile1482Met	missense_variant	Exon 35 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4428C>G	p.Ile1476Met	missense_variant	Exon 34 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4428C>G	p.Ile1476Met	missense_variant	Exon 34 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4401C>G	p.Ile1467Met	missense_variant	Exon 32 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4446C>G	p.Ile1482Met	missense_variant	Exon 35 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4401C>G	p.Ile1467Met	missense_variant	Exon 34 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2283C>G	p.Ile761Met	missense_variant	Exon 16 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1773C>G	p.Ile591Met	missense_variant	Exon 13 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1380C>G	p.Ile460Met	missense_variant	Exon 11 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461310 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111532

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;.;.;.;.;T;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.033	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;N;.;.;.;.
PhyloP100		-4.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.56	N;N;.;N;.;.;.;.;N;.;.
REVEL	Benign	0.26
Sift	Benign	0.030	D;D;.;D;.;.;.;.;D;.;.
Sift4G	Uncertain	0.019	D;D;.;D;.;.;.;.;D;.;.
Polyphen		0.81	.;.;.;.;.;.;P;.;.;.;.
Vest4		0.61
MutPred		0.31		.;.;.;.;.;.;Loss of ubiquitination at K1486 (P = 0.1278);.;.;.;.;
MVP		0.30
MPC		1.3
ClinPred		0.65	D
GERP RS		-8.9
PromoterAI		-0.060	Neutral
Varity_R		0.10
gMVP		0.35
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192863290; hg19: chr3-4741562;