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GeneBe

rs1127354

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

3
7
8

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]

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: {Benign=2, Likely_benign=1, 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 UniProt
ITPANM_033453.4 linkuse as main transcriptc.94C>A p.Pro32Thr missense_variant 2/8 ENST00000380113.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ITPAENST00000380113.8 linkuse as main transcriptc.94C>A p.Pro32Thr missense_variant 2/81 NM_033453.4 P1Q9BY32-1

Frequencies

GnomAD3 genomes
AF:
0.0643
AC:
9779
AN:
152138
Hom.:
389
Cov.:
32
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.:
32
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.:
32
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
Affects, no assertion criteria providedliterature onlyOMIMSep 25, 2009- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 10, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021This 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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
T
BayesDel_noAF
Uncertain
0.040
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
D;D
MetaRNN
Benign
0.0018
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
0.0000014
P;P;P
PrimateAI
Uncertain
0.64
T
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
T
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.

Other links and lift over

dbSNP: rs1127354; hg19: chr20-3193842; COSMIC: COSV66318275; COSMIC: COSV66318275; API