rs1553681758

chr3-4665282-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 id is 2579948.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ITPR1
• 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 id is 521315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.1699T>C	p.Tyr567His	missense_variant	17/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.1654T>C	p.Tyr552His	missense_variant	16/61
ITPR1	NM_001099952.4	c.1699T>C	p.Tyr567His	missense_variant	17/59
ITPR1	NM_002222.7	c.1654T>C	p.Tyr552His	missense_variant	16/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.1699T>C	p.Tyr567His	missense_variant	17/62		NM_001378452.1

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2017

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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
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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
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
Polyphen		1.0	.;.;.;.;.;.;D;.;.
Vest4		0.89
MutPred		0.51		Gain of disorder (P = 0.0379);.;Gain of disorder (P = 0.0379);.;Gain of disorder (P = 0.0379);.;Gain of disorder (P = 0.0379);.;.;
MVP		0.92
MPC		2.0
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553681758; hg19: chr3-4706966;