3-4766606-T-C

Position:

• chr3-4766606-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.5621T>C​(p.Val1874Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08106601).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5621T>C	p.Val1874Ala	missense_variant	45/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5576T>C	p.Val1859Ala	missense_variant	44/61		NP_001161744.1
ITPR1	NM_001099952.4	c.5477T>C	p.Val1826Ala	missense_variant	42/59		NP_001093422.2
ITPR1	NM_002222.7	c.5432T>C	p.Val1811Ala	missense_variant	41/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5621T>C	p.Val1874Ala	missense_variant	45/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5597T>C	p.Val1866Ala	missense_variant	45/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5594T>C	p.Val1865Ala	missense_variant	45/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5579T>C	p.Val1860Ala	missense_variant	44/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5576T>C	p.Val1859Ala	missense_variant	44/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5549T>C	p.Val1850Ala	missense_variant	42/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5477T>C	p.Val1826Ala	missense_variant	42/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5432T>C	p.Val1811Ala	missense_variant	41/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3383T>C	p.Val1128Ala	missense_variant	25/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2921T>C	p.Val974Ala	missense_variant	23/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2528T>C	p.Val843Ala	missense_variant	21/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.34	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T;T;T;T;T;T;T;T;.;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.55	.;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.030	N;N;.;N;.;.;.;.;N;.
REVEL	Benign	0.25
Sift	Benign	0.76	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.74	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0020	.;.;.;.;.;.;B;.;.;.
Vest4		0.11
MutPred		0.24		.;.;.;.;.;.;Loss of helix (P = 0.0444);.;.;.;
MVP		0.24
MPC		0.17
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.028
gMVP		0.18

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: rs143093165; hg19: chr3-4808290; COSMIC: COSV56980969; COSMIC: COSV56980969;