NM_033453.4:c.138G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_033453.4(ITPA):c.138G>A(p.Gln46Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,613,556 control chromosomes in the GnomAD database, including 89,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10152 hom., cov: 31)

Exomes 𝑓: 0.32 ( 79777 hom. )

Consequence

ITPA
NM_033453.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.99

Publications

48 publications found

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 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 20-3213332-G-A is Benign according to our data. Variant chr20-3213332-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPA	NM_033453.4 link	c.138G>A	p.Gln46Gln	synonymous_variant	Exon 3 of 8	ENST00000380113.8	NP_258412.1	Q9BY32-1A0A0S2Z3W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8 link	c.138G>A	p.Gln46Gln	synonymous_variant	Exon 3 of 8	1	NM_033453.4	ENSP00000369456.3		Q9BY32-1

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53250

AN:

151798

Hom.:

10135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.457

Gnomad AMI

AF:

0.440

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.587

Gnomad SAS

AF:

0.552

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.367

GnomAD2 exomes

AF:

0.346

AC:

86946

AN:

251486

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.592

Gnomad FIN exome

AF:

0.198

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.326

GnomAD4 exome

AF:

0.319

AC:

466408

AN:

1461640

Hom.:

79777

Cov.:

AF XY:

0.325

AC XY:

235967

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.466

AC:

15617

AN:

33478

American (AMR)

AF:

0.279

AC:

12474

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

7494

AN:

26136

East Asian (EAS)

AF:

0.596

AC:

23662

AN:

39698

South Asian (SAS)

AF:

0.536

AC:

46211

AN:

86258

European-Finnish (FIN)

AF:

0.202

AC:

10793

AN:

53418

Middle Eastern (MID)

AF:

0.386

AC:

2226

AN:

5762

European-Non Finnish (NFE)

AF:

0.294

AC:

327278

AN:

1111774

Other (OTH)

AF:

0.342

AC:

20653

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18650

37300

55949

74599

93249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11162

22324

33486

44648

55810

<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:

0.351

AC:

53307

AN:

151916

Hom.:

10152

Cov.:

AF XY:

0.349

AC XY:

25910

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.457

AC:

18932

AN:

41408

American (AMR)

AF:

0.284

AC:

4336

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1035

AN:

3466

East Asian (EAS)

AF:

0.587

AC:

3021

AN:

5150

South Asian (SAS)

AF:

0.551

AC:

2646

AN:

4800

European-Finnish (FIN)

AF:

0.191

AC:

2018

AN:

10580

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.295

AC:

20028

AN:

67954

Other (OTH)

AF:

0.371

AC:

781

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1652

3304

4956

6608

8260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.318

Hom.:

17663

Bravo

AF:

0.358

Asia WGS

AF:

0.594

AC:

2063

AN:

3478

EpiCase

AF:

0.300

EpiControl

AF:

0.299

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 38% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 35. Only high quality variants are reported. -

Dec 16, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ITPA c.138G>A results in a synonymous change. The variant allele was found at a frequency of 0.35 in 251486 control chromosomes in the gnomAD database, including 17111 homozygotes. The observed variant frequency is approximately 309.23 fold of the estimated maximal expected allele frequency for a pathogenic variant in ITPA causing Early Infantile Epileptic Encephalopathy, 35 phenotype (0.0011), strongly suggesting that the variant is benign. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Inosine triphosphatase deficiency

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.9

(source)

DANN

Benign

0.66

PhyloP100

2.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over