rs1553681758

Variant names:

• chr3-4665282-T-C
• rs1553681758
• NM_001378452.1:c.1699T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_001378452.1(ITPR1):​c.1699T>C​(p.Tyr567His) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y567C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.95
• 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4665283-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2579948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 3-4665282-T-C is Pathogenic according to our data. Variant chr3-4665282-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521315.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.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1654T>C	p.Tyr552His	missense_variant	Exon 16 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1654T>C	p.Tyr552His	missense_variant	Exon 16 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1654T>C	p.Tyr552His	missense_variant	Exon 16 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1654T>C	p.Tyr552His	missense_variant	Exon 16 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1654T>C	p.Tyr552His	missense_variant	Exon 14 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1699T>C	p.Tyr567His	missense_variant	Exon 17 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1654T>C	p.Tyr552His	missense_variant	Exon 16 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Aug 02, 2017

Ambry Genetics

Significance: Likely pathogenic

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	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;M;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;.;.;.;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;D;.;.;.;.;D
Vest4		0.89
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.79
Mutation Taster		=29/71	disease causing (ClinVar)

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: rs1553681758; hg19: chr3-4706966;