rs61757110

Positions:

• chr3-4693723-C-A
• chr3-4693723-C-G
• chr3-4693723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378452.1(ITPR1):​c.4263C>A​(p.His1421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37755185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4263C>A	p.His1421Gln	missense_variant	33/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4218C>A	p.His1406Gln	missense_variant	32/61		NP_001161744.1
ITPR1	NM_001099952.4	c.4236C>A	p.His1412Gln	missense_variant	33/59		NP_001093422.2
ITPR1	NM_002222.7	c.4191C>A	p.His1397Gln	missense_variant	32/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4263C>A	p.His1421Gln	missense_variant	33/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4236C>A	p.His1412Gln	missense_variant	33/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4236C>A	p.His1412Gln	missense_variant	33/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4218C>A	p.His1406Gln	missense_variant	32/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4218C>A	p.His1406Gln	missense_variant	32/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4191C>A	p.His1397Gln	missense_variant	30/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4236C>A	p.His1412Gln	missense_variant	33/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4191C>A	p.His1397Gln	missense_variant	32/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2073C>A	p.His691Gln	missense_variant	14/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1563C>A	p.His521Gln	missense_variant	11/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1170C>A	p.His390Gln	missense_variant	9/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.79
MutPred		0.37		.;.;.;.;.;.;Loss of catalytic residue at D1423 (P = 0.1755);.;.;.;
MVP		0.84
MPC		1.5
ClinPred		0.99	D
GERP RS		-9.2
Varity_R		0.68
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4735407;