rs7270101

Positions:

• chr20-3213247-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

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
• Clinical Significance: drug response reviewed by expert panel B:3 O:2
• Conservation: PhyloP100: 0.323

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 20-3213247-A-C is Benign according to our data. Variant chr20-3213247-A-C is described in ClinVar as [drug_response]. Clinvar id is 14747.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=3, drug_response=1}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPA	NM_033453.4	c.124+21A>C		intron_variant		ENST00000380113.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPA	ENST00000380113.8	c.124+21A>C		intron_variant		1	NM_033453.4	P1

Frequencies

GnomAD3 genomes AF: 0.0960 AC: 14592 AN: 152070 Hom.: 822 Cov.: 32

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

GnomAD3 exomes AF: 0.0873 AC: 21964 AN: 251474 Hom.: 1189 AF XY: 0.0866 AC XY: 11769 AN XY: 135918

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 SAS exome AF: 0.0291

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.: 35 AF XY: 0.115 AC XY: 83336 AN XY: 727202

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.0729

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0308

Gnomad4 FIN exome AF: 0.0780

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0959 AC: 14593 AN: 152188 Hom.: 823 Cov.: 32 AF XY: 0.0912 AC XY: 6784 AN XY: 74404

Gnomad4 AFR AF: 0.0727

Gnomad4 AMR AF: 0.0924

Gnomad4 ASJ AF: 0.0806

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0645

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.105

Alfa AF: 0.109 Hom.: 231

Bravo AF: 0.0980

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:3 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Inosine triphosphatase deficiency Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Affects, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

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

Developmental and epileptic encephalopathy, 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

peginterferon alfa-2b and ribavirin response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs7270101; hg19: chr20-3193893; COSMIC: COSV66318589; COSMIC: COSV66318589;