rs1127354

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

The NM_033453.4(ITPA):c.94C>A(p.Pro32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0751 in 1,613,804 control chromosomes in the GnomAD database, including 5,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. P32P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.064 ( 387 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4730 hom. )

Consequence

ITPA
NM_033453.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:3O:2

Conservation

PhyloP100: 6.18

Variant links:

Genes affected

ITPA (HGNC:6176): (inosine triphosphatase) This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ITPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001791209).

BP6

Variant 20-3213196-C-A is Benign according to our data. Variant chr20-3213196-C-A is described in ClinVar as [drug_response]. Clinvar id is 14746.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, drug_response=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPA	NM_033453.4 linkuse as main transcript	c.94C>A	p.Pro32Thr	missense_variant	2/8	ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8 linkuse as main transcript	c.94C>A	p.Pro32Thr	missense_variant	2/8	1	NM_033453.4	ENSP00000369456	P1	Q9BY32-1

Frequencies

GnomAD3 genomes

AF:

0.0643

AC:

9779

AN:

152138

Hom.:

389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0442

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.0366

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.0482

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0726

Gnomad OTH

AF:

0.0588

GnomAD3 exomes

AF:

0.0752

AC:

18912

AN:

251492

Hom.:

971

AF XY:

0.0788

AC XY:

10708

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0455

Gnomad AMR exome

AF:

0.0266

Gnomad ASJ exome

AF:

0.0725

Gnomad EAS exome

AF:

0.171

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.0537

Gnomad NFE exome

AF:

0.0706

Gnomad OTH exome

AF:

0.0795

GnomAD4 exome

AF:

0.0762

AC:

111346

AN:

1461548

Hom.:

4730

Cov.:

AF XY:

0.0776

AC XY:

56419

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0434

Gnomad4 AMR exome

AF:

0.0292

Gnomad4 ASJ exome

AF:

0.0713

Gnomad4 EAS exome

AF:

0.153

Gnomad4 SAS exome

AF:

0.122

Gnomad4 FIN exome

AF:

0.0569

Gnomad4 NFE exome

AF:

0.0738

Gnomad4 OTH exome

AF:

0.0784

GnomAD4 genome

AF:

0.0642

AC:

9777

AN:

152256

Hom.:

387

Cov.:

AF XY:

0.0644

AC XY:

4793

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0441

Gnomad4 AMR

AF:

0.0366

Gnomad4 ASJ

AF:

0.0695

Gnomad4 EAS

AF:

0.174

Gnomad4 SAS

AF:

0.123

Gnomad4 FIN

AF:

0.0482

Gnomad4 NFE

AF:

0.0726

Gnomad4 OTH

AF:

0.0577

Alfa

AF:

0.0738

Hom.:

797

Bravo

AF:

0.0613

TwinsUK

AF:

0.0685

AC:

254

ALSPAC

AF:

0.0695

AC:

268

ESP6500AA

AF:

0.0422

AC:

186

ESP6500EA

AF:

0.0677

AC:

582

ExAC

AF:

0.0771

AC:

9360

Asia WGS

AF:

0.104

AC:

360

AN:

3478

EpiCase

AF:

0.0701

EpiControl

AF:

0.0720

ClinVar

Significance: drug response

Submissions summary: Benign:3Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inosine triphosphatase deficiency

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Affects, no assertion criteria provided	literature only	OMIM	Sep 25, 2009	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 10, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 17113761, 22060550, 22613675, 19914375, 24621321, 23528839, 19631656, 25525159, 22939045, 20173735, 21659334, 19682085, 23547827, 20547162, 20637204, 12384777, 27703193, 26394463, 30106365, 19579612) -

peginterferon alfa-2b and ribavirin response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.0000014

P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.31

Sift

Benign

0.094

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0020

B;.

Vest4

0.29

MPC

0.88

ClinPred

0.027

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.71

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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