rs1553740488

Variant names:

• chr3-4775417-G-C
• rs1553740488
• NM_001378452.1:c.6155G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378452.1(ITPR1):​c.6155G>C​(p.Cys2052Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.91
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6155G>C	p.Cys2052Ser	missense_variant	Exon 47 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6110G>C	p.Cys2037Ser	missense_variant	Exon 46 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6011G>C	p.Cys2004Ser	missense_variant	Exon 44 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5966G>C	p.Cys1989Ser	missense_variant	Exon 43 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6155G>C	p.Cys2052Ser	missense_variant	Exon 47 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6131G>C	p.Cys2044Ser	missense_variant	Exon 47 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6128G>C	p.Cys2043Ser	missense_variant	Exon 47 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6113G>C	p.Cys2038Ser	missense_variant	Exon 46 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6110G>C	p.Cys2037Ser	missense_variant	Exon 46 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6083G>C	p.Cys2028Ser	missense_variant	Exon 44 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6011G>C	p.Cys2004Ser	missense_variant	Exon 44 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5966G>C	p.Cys1989Ser	missense_variant	Exon 43 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3917G>C	p.Cys1306Ser	missense_variant	Exon 27 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3455G>C	p.Cys1152Ser	missense_variant	Exon 25 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3062G>C	p.Cys1021Ser	missense_variant	Exon 23 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460830 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726622

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 85940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111514

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;.;.;.;.;.;M;.;.;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.2	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.010	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.83
MutPred		0.82		.;.;.;.;.;.;Gain of disorder (P = 3e-04);.;.;.;
MVP		0.92
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.95
Mutation Taster		=14/86	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: rs1553740488; hg19: chr3-4817101;