3-4733168-C-G

Position:

• chr3-4733168-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.5301C>G​(p.Ser1767Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,672 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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 (HGNC:):

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=0.17495382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5301C>G	p.Ser1767Arg	missense_variant	43/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5256C>G	p.Ser1752Arg	missense_variant	42/61		NP_001161744.1
ITPR1	NM_001099952.4	c.5157C>G	p.Ser1719Arg	missense_variant	40/59		NP_001093422.2
ITPR1	NM_002222.7	c.5112C>G	p.Ser1704Arg	missense_variant	39/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5301C>G	p.Ser1767Arg	missense_variant	43/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5277C>G	p.Ser1759Arg	missense_variant	43/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5274C>G	p.Ser1758Arg	missense_variant	43/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5259C>G	p.Ser1753Arg	missense_variant	42/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5256C>G	p.Ser1752Arg	missense_variant	42/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5229C>G	p.Ser1743Arg	missense_variant	40/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5157C>G	p.Ser1719Arg	missense_variant	40/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5112C>G	p.Ser1704Arg	missense_variant	39/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3063C>G	p.Ser1021Arg	missense_variant	23/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2601C>G	p.Ser867Arg	missense_variant	21/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2208C>G	p.Ser736Arg	missense_variant	19/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249120 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727122

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	.;.;.;.;.;.;T;.;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;L;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;N;N;N;.;.;.;.;N;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.35	T;T;T;T;.;.;.;.;T;.;.
Sift4G	Benign	0.50	T;T;.;T;.;.;.;.;T;.;.
Polyphen		0.0020	.;.;.;.;.;.;B;.;.;.;.
Vest4		0.57
MutPred		0.21		.;.;.;.;.;.;Gain of MoRF binding (P = 0.0152);.;.;.;.;
MVP		0.96
MPC		0.19
ClinPred		0.23	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs758372914; hg19: chr3-4774852;