rs1553706329

Variant names:

• chr3-4711790-A-C
• rs1553706329
• NM_001378452.1:c.5025A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001378452.1(ITPR1):​c.5025A>C​(p.Glu1675Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1675K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.553
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1270302).
• BP6: Variant 3-4711790-A-C is Benign according to our data. Variant chr3-4711790-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 503527.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5025A>C	p.Glu1675Asp	missense_variant	Exon 39 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4980A>C	p.Glu1660Asp	missense_variant	Exon 38 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.4998A>C	p.Glu1666Asp	missense_variant	Exon 39 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.4953A>C	p.Glu1651Asp	missense_variant	Exon 38 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5025A>C	p.Glu1675Asp	missense_variant	Exon 39 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4998A>C	p.Glu1666Asp	missense_variant	Exon 39 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4998A>C	p.Glu1666Asp	missense_variant	Exon 39 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4980A>C	p.Glu1660Asp	missense_variant	Exon 38 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4980A>C	p.Glu1660Asp	missense_variant	Exon 38 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4953A>C	p.Glu1651Asp	missense_variant	Exon 36 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4998A>C	p.Glu1666Asp	missense_variant	Exon 39 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4953A>C	p.Glu1651Asp	missense_variant	Exon 38 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2835A>C	p.Glu945Asp	missense_variant	Exon 20 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2325A>C	p.Glu775Asp	missense_variant	Exon 17 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1932A>C	p.Glu644Asp	missense_variant	Exon 15 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 29 Benign:1

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.56	.;.;.;.;.;.;D;.;.;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;.;.;.;.;L;.;.;.;.
PhyloP100		0.55
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.0	N;N;.;N;.;.;.;.;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.20	T;T;.;T;.;.;.;.;T;.;.
Sift4G	Benign	0.23	T;T;.;T;.;.;.;.;T;.;.
Polyphen		0.090	.;.;.;.;.;.;B;.;.;.;.
Vest4		0.59
MutPred		0.17		.;.;.;.;.;.;Loss of ubiquitination at K1670 (P = 0.069);.;.;.;.;
MVP		0.62
MPC		1.7
ClinPred		0.52	D
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.39
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1553706329; hg19: chr3-4753474;