3-4516581-G-T

Position:

• chr3-4516581-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.90G>T​(p.Leu30Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense, splice_region
• Scores: Splicing: ADA: 0.1043
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/61		NP_001161744.1
ITPR1	NM_001099952.4	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/59		NP_001093422.2
ITPR1	NM_002222.7	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	1/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.90G>T	p.Leu30Phe	missense_variant, splice_region_variant	3/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 03, 2024

Variant summary: ITPR1 c.90G>T (p.Leu30Phe) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821), which corresponds to the ligand binding region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located close to a splice-site: consensus agreement among computation tools predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 241860 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.90G>T in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;M;.;.;.;M;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.61
MutPred		0.72		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.92
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.58
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.40
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4558265;