3-4673386-G-T

Variant names:

• chr3-4673386-G-T
• rs200199463
• NM_001378452.1:c.2455G>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 in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 20 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 20 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 20 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 20 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 18 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2455G>T	p.Asp819Tyr	missense_variant, splice_region_variant	Exon 21 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2410G>T	p.Asp804Tyr	missense_variant, splice_region_variant	Exon 20 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.292G>T	p.Asp98Tyr	missense_variant, splice_region_variant	Exon 2 of 42			ENSP00000497872.1

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

Aug 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Pathogenic	0.93	.;.;.;.;.;.;D;.;.;.
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;.;.;.
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;