rs1553681680

Positions:

• chr3-4665189-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_001378452.1(ITPR1):​c.1606C>T​(p.Leu536Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.912

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ITPR1
• BP6: Variant 3-4665189-C-T is Benign according to our data. Variant chr3-4665189-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 503528.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.1606C>T	p.Leu536Phe	missense_variant	17/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.1561C>T	p.Leu521Phe	missense_variant	16/61
ITPR1	NM_001099952.4	c.1606C>T	p.Leu536Phe	missense_variant	17/59
ITPR1	NM_002222.7	c.1561C>T	p.Leu521Phe	missense_variant	16/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.1606C>T	p.Leu536Phe	missense_variant	17/62		NM_001378452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Likely benign, criteria provided, single submitter

research

Schule lab, Hertie Institute for Clinical Brain Research

Feb 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.7	L;.;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D;D;D;D;.;.;.;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.010	D;T;T;D;.;.;.;.;T
Sift4G	Uncertain	0.013	D;D;.;D;.;.;.;.;D
Polyphen		0.93	.;.;.;.;.;.;P;.;.
Vest4		0.66
MutPred		0.62		Loss of stability (P = 0.1386);.;Loss of stability (P = 0.1386);.;Loss of stability (P = 0.1386);.;Loss of stability (P = 0.1386);.;.;
MVP		0.73
MPC		1.8
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.28
gMVP		0.46

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: rs1553681680; hg19: chr3-4706873; COSMIC: COSV56992784;