3-4670904-C-G

Variant names:

• chr3-4670904-C-G
• rs878853172
• NM_001378452.1:c.2182C>G

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.2182C>G​(p.Arg728Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R728Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 4 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=0.20651239).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.2182C>G	p.Arg728Gly	missense	Exon 20 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.2137C>G	p.Arg713Gly	missense	Exon 19 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.2182C>G	p.Arg728Gly	missense	Exon 20 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.2182C>G	p.Arg728Gly	missense	Exon 20 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.2182C>G	p.Arg728Gly	missense	Exon 20 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.2182C>G	p.Arg728Gly	missense	Exon 20 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441550 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 714138

African (AFR) AF: 0.00 AC: 0 AN: 32994

American (AMR) AF: 0.00 AC: 0 AN: 42958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 83246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5202

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100226

Other (OTH) AF: 0.00 AC: 0 AN: 59474

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Benign	0.37	T
Sift4G	Benign	0.42	T
Polyphen		0.013	B
Vest4		0.57
MutPred		0.44		Loss of helix (P = 0.0376)
MVP		0.93
MPC		0.97
ClinPred		0.29	T
GERP RS		3.7
PromoterAI		0.0054	Neutral
Varity_R		0.083
gMVP		0.59
Mutation Taster		=71/29	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: rs878853172; hg19: chr3-4712588;