rs150904363

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033453.4(ITPA):c.233A>G(p.Asn78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,614,174 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N78I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00088 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 8 hom. )

Consequence

ITPA
NM_033453.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.78

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012376815).

BP6

Variant 20-3214028-A-G is Benign according to our data. Variant chr20-3214028-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 464829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00088 (134/152286) while in subpopulation SAS AF = 0.000622 (3/4826). AF 95% confidence interval is 0.000457. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPA	NM_033453.4 link	c.233A>G	p.Asn78Ser	missense_variant	Exon 4 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.233A>G	p.Asn78Ser	missense_variant	Exon 4 of 8	1	NM_033453.4	ENSP00000369456.3		Q9BY32-1

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00132

AC:

331

AN:

251478

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000580

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000796

AC:

1163

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

596

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000738

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

496

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.000719

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000407

AC:

453

AN:

1112006

Other (OTH)

AF:

0.00157

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

142

214

285

356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000880

AC:

134

AN:

152286

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41566

American (AMR)

AF:

0.000589

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00145

Hom.:

Bravo

AF:

0.000873

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00118

AC:

143

EpiCase

AF:

0.00104

EpiControl

AF:

0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inosine triphosphatase deficiency

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ITPA-related disorder

Benign:1

Aug 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.

Eigen

Benign

0.078

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.0059

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.8

M;.;.

PhyloP100

2.8

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Benign

0.16

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.031

D;D;T

Polyphen

0.016

B;.;.

Vest4

0.23

MVP

0.55

MPC

0.24

ClinPred

0.046

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.50

Mutation Taster

=93/7

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over