Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_033453.4(ITPA):c.278A>G(p.Glu93Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,920 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. E93Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 10 hom. )

Consequence

ITPA
NM_033453.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.77

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_033453.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008969754).

BP6

Variant 20-3215295-A-G is Benign according to our data. Variant chr20-3215295-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00579 (881/152242) while in subpopulation AFR AF = 0.0202 (838/41538). AF 95% confidence interval is 0.019. There are 7 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

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	HGVSp	Effect	Exon Rank	Protein
ITPA	NM_033453.4	MANE Select	c.278A>G	p.Glu93Gly	missense	Exon 5 of 8	NP_258412.1
ITPA	NM_001424408.1		c.278A>G	p.Glu93Gly	missense	Exon 5 of 9	NP_001411337.1
ITPA	NM_001424409.1		c.404A>G	p.Glu135Gly	missense	Exon 6 of 9	NP_001411338.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ITPA	ENST00000380113.8	TSL:1 MANE Select	c.278A>G	p.Glu93Gly	missense	Exon 5 of 8	ENSP00000369456.3
ITPA	ENST00000455664.6	TSL:1	c.227A>G	p.Glu76Gly	missense	Exon 5 of 8	ENSP00000413282.1
ITPA	ENST00000399838.3	TSL:1	c.155A>G	p.Glu52Gly	missense	Exon 3 of 6	ENSP00000382732.3

Frequencies

GnomAD3 genomes

AF:

0.00579

AC:

881

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00146

AC:

366

AN:

251454

AF XY:

0.000979

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000560

AC:

819

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

368

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0202

AC:

676

AN:

33470

American (AMR)

AF:

0.00130

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111834

Other (OTH)

AF:

0.00106

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

116

155

194

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:

0.00579

AC:

881

AN:

152242

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

401

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0202

AC:

838

AN:

41538

American (AMR)

AF:

0.00190

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

153

204

255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00237

Hom.:

Bravo

AF:

0.00655

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00186

AC:

226

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inosine triphosphatase deficiency (1)

Inosine triphosphatase deficiency;C4225256:Developmental and epileptic encephalopathy, 35 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Benign

-0.043

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.68

PhyloP100

5.8

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.0

REVEL

Benign

0.11

Sift

Uncertain

0.029

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.29

MVP

0.48

MPC

0.34

ClinPred

0.035

GERP RS

4.7

Varity_R

0.46

gMVP

0.57

Mutation Taster

=87/13

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over