3-4516493-T-C

Position:

• chr3-4516493-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001378452.1(ITPR1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,407,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2T>C	p.Met1?	start_lost	3/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2T>C	p.Met1?	start_lost	3/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2T>C	p.Met1?	start_lost	3/59		NP_001093422.2
ITPR1	NM_002222.7	c.2T>C	p.Met1?	start_lost	3/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2T>C	p.Met1?	start_lost	3/62		NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1407762 Hom.: 0 Cov.: 26 AF XY: 0.00000143 AC XY: 1 AN XY: 700830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2018

This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 5, this would result in loss of first 4 amino acids from the N-terminal suppressor domain of the ITPR1 protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with ITPR1-related disease. However, this variant has been observed to be de novo in an individual affected with clinical features of spinocerebellar ataxia type 29 (SCA29) (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the ITPR1 mRNA. The next in-frame methionine is located at codon 5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	0.77	N;N;N;N;N;N;N
PROVEAN	Uncertain	-3.1	D;D;.;D;D;.;N;.;.;.;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		0.72, 0.99	.;.;.;.;.;.;P;.;D;.;.
Vest4		0.90
MutPred		0.99		Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);Gain of phosphorylation at M1 (P = 0.022);
MVP		0.97
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.81
gMVP		0.62

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: rs1575381029; hg19: chr3-4558177;