3-4645672-A-G

Position:

• chr3-4645672-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.799A>G​(p.Thr267Ala) 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: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.799A>G	p.Thr267Ala	missense_variant	10/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.799A>G	p.Thr267Ala	missense_variant	10/61		NP_001161744.1
ITPR1	NM_001099952.4	c.799A>G	p.Thr267Ala	missense_variant	10/59		NP_001093422.2
ITPR1	NM_002222.7	c.799A>G	p.Thr267Ala	missense_variant	10/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.799A>G	p.Thr267Ala	missense_variant	10/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.799A>G	p.Thr267Ala	missense_variant	10/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.799A>G	p.Thr267Ala	missense_variant	10/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.799A>G	p.Thr267Ala	missense_variant	10/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.799A>G	p.Thr267Ala	missense_variant	10/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.799A>G	p.Thr267Ala	missense_variant	8/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.799A>G	p.Thr267Ala	missense_variant	10/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.799A>G	p.Thr267Ala	missense_variant	10/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jun 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.7	D;D;.;D;D;.;N;.;.;.;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		0.98, 1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.82
MutPred		0.64		Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);
MVP		0.94
MPC		1.8
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.78

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: rs1553666615; hg19: chr3-4687356;