3-4673386-G-T

Variant summary

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

The NM_001378452.1(ITPR1):c.2455G>T(p.Asp819Tyr) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense, splice_region
• Scores: Splicing: ADA: 0.9663
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91

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 where missense usually causes diseases, ITPR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	21/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	20/61
ITPR1	NM_001099952.4	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	21/59
ITPR1	NM_002222.7	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	20/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	21/62		NM_001378452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

The c.2410G>T (p.D804Y) alteration is located in exon 20 (coding exon 18) of the ITPR1 gene. This alteration results from a G to T substitution at nucleotide position 2410, causing the aspartic acid (D) at amino acid position 804 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;.;.;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;D;D;D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.98
MutPred		0.35		Loss of disorder (P = 0.0309);.;Loss of disorder (P = 0.0309);.;Loss of disorder (P = 0.0309);.;Loss of disorder (P = 0.0309);.;.;.;
MVP		0.90
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.040		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: rs200199463; hg19: chr3-4715070;