20-3213247-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033453.4(ITPA):c.124+21A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,972 control chromosomes in the GnomAD database, including 11,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.096 ( 823 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11012 hom. )

Consequence

ITPA
NM_033453.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.323

Publications

177 publications found

Variant links:

COSMIC-nc: COSV66318589

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 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 35
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
inosine triphosphatase deficiency
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ITPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033453.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITPA	NM_033453.4	MANE Select	c.124+21A>C	intron	N/A	NP_258412.1
ITPA	NM_001424408.1		c.124+21A>C	intron	N/A	NP_001411337.1
ITPA	NM_001424409.1		c.250+21A>C	intron	N/A	NP_001411338.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITPA	ENST00000380113.8	TSL:1 MANE Select	c.124+21A>C	intron	N/A	ENSP00000369456.3
ITPA	ENST00000455664.6	TSL:1	c.73+21A>C	intron	N/A	ENSP00000413282.1
ITPA	ENST00000399838.3	TSL:1	c.67-738A>C	intron	N/A	ENSP00000382732.3

Frequencies

GnomAD3 genomes

AF:

0.0960

AC:

14592

AN:

152070

Hom.:

822

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0727

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0926

Gnomad ASJ

AF:

0.0806

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0247

Gnomad FIN

AF:

0.0645

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.0873

AC:

21964

AN:

251474

AF XY:

0.0866

show subpopulations

Gnomad AFR exome

AF:

0.0721

Gnomad AMR exome

AF:

0.0700

Gnomad ASJ exome

AF:

0.0760

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0729

Gnomad NFE exome

AF:

0.127

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.118

AC:

171805

AN:

1461784

Hom.:

11012

Cov.:

AF XY:

0.115

AC XY:

83336

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0732

AC:

2452

AN:

33480

American (AMR)

AF:

0.0729

AC:

3260

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0781

AC:

2042

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0308

AC:

2657

AN:

86258

European-Finnish (FIN)

AF:

0.0780

AC:

4166

AN:

53420

Middle Eastern (MID)

AF:

0.0815

AC:

470

AN:

5768

European-Non Finnish (NFE)

AF:

0.135

AC:

150519

AN:

1111908

Other (OTH)

AF:

0.103

AC:

6233

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

8908

17816

26725

35633

44541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5344

10688

16032

21376

26720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0959

AC:

14593

AN:

152188

Hom.:

823

Cov.:

AF XY:

0.0912

AC XY:

6784

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0727

AC:

3018

AN:

41528

American (AMR)

AF:

0.0924

AC:

1412

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0806

AC:

280

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5176

South Asian (SAS)

AF:

0.0247

AC:

119

AN:

4822

European-Finnish (FIN)

AF:

0.0645

AC:

684

AN:

10598

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.130

AC:

8806

AN:

67990

Other (OTH)

AF:

0.105

AC:

223

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

687

1375

2062

2750

3437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.113

Hom.:

1662

Bravo

AF:

0.0980

Asia WGS

AF:

0.0180

AC:

AN:

3478

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

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2002

OMIM

Significance:Affects

Review Status:no assertion criteria provided

Collection Method:literature only

Developmental and epileptic encephalopathy, 35

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

May 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19579612, 12384777, 20547162, 22613675, 17113761, 20173735, 22939045)

peginterferon alfa-2b and ribavirin response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over