3-4814509-G-C

Position:

• chr3-4814509-G-C

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.7648G>C​(p.Gly2550Arg) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• 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]

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, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7648G>C	p.Gly2550Arg	missense_variant	58/62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7648G>C	p.Gly2550Arg	missense_variant	58/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7624G>C	p.Gly2542Arg	missense_variant	58/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7621G>C	p.Gly2541Arg	missense_variant	58/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7606G>C	p.Gly2536Arg	missense_variant	57/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7603G>C	p.Gly2535Arg	missense_variant	57/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7576G>C	p.Gly2526Arg	missense_variant	55/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7504G>C	p.Gly2502Arg	missense_variant	55/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7459G>C	p.Gly2487Arg	missense_variant	54/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5410G>C	p.Gly1804Arg	missense_variant	38/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4825G>C	p.Gly1609Arg	missense_variant	35/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4588G>C	p.Gly1530Arg	missense_variant	35/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 29

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

Apr 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;.;D;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;.;D;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.
Vest4		0.97
MutPred		0.72		.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0508);.;.;.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.93
gMVP		1.0

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: rs1553757628; hg19: chr3-4856193;