Variant chr3-4766606-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.59

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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
ITPR1	NM_001378452.1 linkuse as main transcript	c.5621T>C	p.Val1874Ala	missense_variant	45/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 linkuse as main transcript	c.5576T>C	p.Val1859Ala	missense_variant	44/61		NP_001161744.1
ITPR1	NM_001099952.4 linkuse as main transcript	c.5477T>C	p.Val1826Ala	missense_variant	42/59		NP_001093422.2
ITPR1	NM_002222.7 linkuse as main transcript	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 linkuse as main transcript	c.5621T>C	p.Val1874Ala	missense_variant	45/62		NM_001378452.1	ENSP00000497605		Q14643-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

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

LINK: link

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

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.34

.;.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.57

T;T;T;T;T;T;T;T;.;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.081

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.55

.;.;.;.;.;.;N;.;.;.

MutationTaster

Benign

0.92

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over