3-4670904-C-G

Position:

• chr3-4670904-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20651239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2182C>G	p.Arg728Gly	missense_variant	20/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2137C>G	p.Arg713Gly	missense_variant	19/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2182C>G	p.Arg728Gly	missense_variant	20/59		NP_001093422.2
ITPR1	NM_002222.7	c.2137C>G	p.Arg713Gly	missense_variant	19/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2182C>G	p.Arg728Gly	missense_variant	20/62		NM_001378452.1	ENSP00000497605

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.;N;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N;N;N;N;.;.;.;.;N;.
REVEL	Uncertain	0.48
Sift	Benign	0.37	T;T;T;T;.;.;.;.;T;.
Sift4G	Benign	0.42	T;T;.;T;.;.;.;.;T;.
Polyphen		0.013	.;.;.;.;.;.;B;.;.;.
Vest4		0.57
MutPred		0.44		Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;.;.;
MVP		0.93
MPC		0.97
ClinPred		0.29	T
GERP RS		3.7
Varity_R		0.083
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853172; hg19: chr3-4712588;