3-4814509-G-C

Variant names:

• chr3-4814509-G-C
• rs1553757628
• NM_001378452.1:c.7648G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• 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
• 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001378452.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7648G>C	p.Gly2550Arg	missense_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

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

Apr 24, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.
PhyloP100		9.5
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
PromoterAI		0.15	Neutral
Varity_R		0.93
gMVP		1.0
Mutation Taster		=6/94	disease causing

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: rs1553757628; hg19: chr3-4856193;