rs1127354

chr20-3213196-C-Achr20-3213196-C-Gchr20-3213196-C-T

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.94C>A(p.Pro32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0751 in 1,613,804 control chromosomes in the GnomAD database, including 5,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. P32P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.064 (387 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4730 hom.)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: drug response reviewed by expert panel B:3 O:2
• Conservation: PhyloP100: 6.18

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 (MetaRNN=0.001791209).
• BP6: Variant 20-3213196-C-A is Benign according to our data. Variant chr20-3213196-C-A is described in ClinVar as [drug_response]. Clinvar id is 14746.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPA	NM_033453.4	c.94C>A	p.Pro32Thr	missense_variant	2/8	ENST00000380113.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPA	ENST00000380113.8	c.94C>A	p.Pro32Thr	missense_variant	2/8	1	NM_033453.4	P1

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9779 AN: 152138 Hom.: 389 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0726

Gnomad OTH AF: 0.0588

GnomAD3 exomes AF: 0.0752 AC: 18912 AN: 251492 Hom.: 971 AF XY: 0.0788 AC XY: 10708 AN XY: 135920

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.0725

Gnomad EAS exome AF: 0.171

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0706

Gnomad OTH exome AF: 0.0795

GnomAD4 exome AF: 0.0762 AC: 111346 AN: 1461548 Hom.: 4730 Cov.: 32 AF XY: 0.0776 AC XY: 56419 AN XY: 727094

Gnomad4 AFR exome AF: 0.0434

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0713

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.0738

Gnomad4 OTH exome AF: 0.0784

GnomAD4 genome AF: 0.0642 AC: 9777 AN: 152256 Hom.: 387 Cov.: 32 AF XY: 0.0644 AC XY: 4793 AN XY: 74438

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0738 Hom.: 797

Bravo AF: 0.0613

TwinsUK AF: 0.0685 AC: 254

ALSPAC AF: 0.0695 AC: 268

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.0677 AC: 582

ExAC AF: 0.0771 AC: 9360

Asia WGS AF: 0.104 AC: 360 AN: 3478

EpiCase AF: 0.0701

EpiControl AF: 0.0720

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

Affects, no assertion criteria provided	literature only	OMIM	Sep 25, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

This variant is associated with the following publications: (PMID: 17113761, 22060550, 22613675, 19914375, 24621321, 23528839, 19631656, 25525159, 22939045, 20173735, 21659334, 19682085, 23547827, 20547162, 20637204, 12384777, 27703193, 26394463, 30106365, 19579612) -

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.0000014	P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.31
Sift	Benign	0.094	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0020	B;.
Vest4		0.29
MPC		0.88
ClinPred		0.027	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.71
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1127354; hg19: chr20-3193842; COSMIC: COSV66318275; COSMIC: COSV66318275;