NM_033453.4:c.138G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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

GnomAD3 exomes

AF:

0.346

AC:

86946

AN:

251486

Hom.:

17111

AF XY:

0.353

AC XY:

48031

AN XY:

135914

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 SAS exome

AF:

0.549

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

Gnomad4 AFR exome

AF:

0.466

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.287

Gnomad4 EAS exome

AF:

0.596

Gnomad4 SAS exome

AF:

0.536

Gnomad4 FIN exome

AF:

0.202

Gnomad4 NFE exome

AF:

0.294

Gnomad4 OTH exome

AF:

0.342

GnomAD4 genome

AF:

0.351

AC:

53307

AN:

151916

Hom.:

10152

Cov.:

AF XY:

0.349

AC XY:

25910

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.457

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.299

Gnomad4 EAS

AF:

0.587

Gnomad4 SAS

AF:

0.551

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.371

Alfa

AF:

0.312

Hom.:

12918

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

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

DANN

Benign

0.66

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over