NM_001378452.1:c.2732C>G

Variant names:

• chr3-4675201-C-G
• rs201519806
• NM_001378452.1:c.2732C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A911V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15317121).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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;.;.;.
PhyloP100		4.5
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
PromoterAI		-0.24	Neutral
Varity_R		0.092
gMVP		0.52
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs201519806; hg19: chr3-4716885;