3-4675201-C-G

Position:

• chr3-4675201-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.2732C>G​(p.Ala911Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15317121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2732C>G	p.Ala911Gly	missense_variant	23/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2687C>G	p.Ala896Gly	missense_variant	22/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2732C>G	p.Ala911Gly	missense_variant	23/59		NP_001093422.2
ITPR1	NM_002222.7	c.2687C>G	p.Ala896Gly	missense_variant	22/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2732C>G	p.Ala911Gly	missense_variant	23/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2732C>G	p.Ala911Gly	missense_variant	23/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2732C>G	p.Ala911Gly	missense_variant	23/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2687C>G	p.Ala896Gly	missense_variant	22/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2687C>G	p.Ala896Gly	missense_variant	22/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2687C>G	p.Ala896Gly	missense_variant	20/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2732C>G	p.Ala911Gly	missense_variant	23/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2687C>G	p.Ala896Gly	missense_variant	22/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.569C>G	p.Ala190Gly	missense_variant	4/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.59C>G	p.Ala20Gly	missense_variant	1/39			ENSP00000498149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N;N;.;.;.;.;N;.
REVEL	Benign	0.21
Sift	Benign	0.39	T;T;T;T;.;.;.;.;T;.
Sift4G	Benign	0.44	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0	.;.;.;.;.;.;B;.;.;.
Vest4		0.15
MutPred		0.34		Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;Loss of helix (P = 0.0444);.;.;.;
MVP		0.41
MPC		0.72
ClinPred		0.38	T
GERP RS		3.8
Varity_R		0.092
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs201519806; hg19: chr3-4716885;