chr3-4516511-G-A

Position:

• chr3-4516511-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001378452.1(ITPR1):​c.20G>A​(p.Ser7Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 4 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). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.744

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.20G>A	p.Ser7Asn	missense_variant	3/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.20G>A	p.Ser7Asn	missense_variant	3/61		NP_001161744.1
ITPR1	NM_001099952.4	c.20G>A	p.Ser7Asn	missense_variant	3/59		NP_001093422.2
ITPR1	NM_002222.7	c.20G>A	p.Ser7Asn	missense_variant	3/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.20G>A	p.Ser7Asn	missense_variant	3/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.20G>A	p.Ser7Asn	missense_variant	3/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.20G>A	p.Ser7Asn	missense_variant	3/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.20G>A	p.Ser7Asn	missense_variant	3/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.20G>A	p.Ser7Asn	missense_variant	3/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.20G>A	p.Ser7Asn	missense_variant	1/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.20G>A	p.Ser7Asn	missense_variant	3/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.20G>A	p.Ser7Asn	missense_variant	3/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

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

Dec 03, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ITPR1 protein function. This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 7 of the ITPR1 protein (p.Ser7Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;N;.;N;N;.;N;.;.;.;N
REVEL	Uncertain	0.63
Sift	Benign	0.10	T;T;.;T;T;.;T;.;.;.;T
Sift4G	Benign	0.11	T;T;.;.;T;.;T;.;.;.;T
Polyphen		0.83, 0.0050	.;.;.;.;.;.;P;.;B;.;.
Vest4		0.68
MutPred		0.70		Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);Gain of catalytic residue at S7 (P = 0.0146);
MVP		0.87
MPC		1.7
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4558195;