rs943946433

Positions:

• chr3-4699840-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.4435C>T​(p.His1479Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., 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: 7.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP6: Variant 3-4699840-C-T is Benign according to our data. Variant chr3-4699840-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 503526.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4435C>T	p.His1479Tyr	missense_variant	35/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4390C>T	p.His1464Tyr	missense_variant	34/61		NP_001161744.1
ITPR1	NM_001099952.4	c.4408C>T	p.His1470Tyr	missense_variant	35/59		NP_001093422.2
ITPR1	NM_002222.7	c.4363C>T	p.His1455Tyr	missense_variant	34/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4435C>T	p.His1479Tyr	missense_variant	35/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4408C>T	p.His1470Tyr	missense_variant	35/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4408C>T	p.His1470Tyr	missense_variant	35/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4390C>T	p.His1464Tyr	missense_variant	34/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4390C>T	p.His1464Tyr	missense_variant	34/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4363C>T	p.His1455Tyr	missense_variant	32/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4408C>T	p.His1470Tyr	missense_variant	35/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4363C>T	p.His1455Tyr	missense_variant	34/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2245C>T	p.His749Tyr	missense_variant	16/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1735C>T	p.His579Tyr	missense_variant	13/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1342C>T	p.His448Tyr	missense_variant	11/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

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 AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.00000378

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	.;.;.;.;.;.;D;.;.;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.9	.;.;.;.;.;.;L;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;D;.;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.84	T;T;.;T;.;.;.;.;T;.;.
Sift4G	Benign	0.95	T;T;.;T;.;.;.;.;T;.;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.;.
Vest4		0.79
MutPred		0.21		.;.;.;.;.;.;Loss of disorder (P = 0.0512);.;.;.;.;
MVP		0.64
MPC		1.9
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.40

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: rs943946433; hg19: chr3-4741524;