rs1127354

Variant names:

• chr20-3213196-C-A
• rs1127354
• NM_033453.4:c.94C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-3213196-C-A
• chr20-3213196-C-G
• chr20-3213196-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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
• Publications: 358 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001791209).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	NM_033453.4	MANE Select	c.94C>A	p.Pro32Thr	missense	Exon 2 of 8	NP_258412.1
	ITPA	NM_001424408.1		c.94C>A	p.Pro32Thr	missense	Exon 2 of 9	NP_001411337.1
	ITPA	NM_001424409.1		c.220C>A	p.Pro74Thr	missense	Exon 3 of 9	NP_001411338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.94C>A	p.Pro32Thr	missense	Exon 2 of 8	ENSP00000369456.3
	ITPA	ENST00000455664.6	TSL:1	c.43C>A	p.Pro15Thr	missense	Exon 2 of 8	ENSP00000413282.1
	ITPA	ENST00000399838.3	TSL:1	c.67-789C>A		intron	N/A	ENSP00000382732.3

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

GnomAD2 exomes AF: 0.0752 AC: 18912 AN: 251492 AF XY: 0.0788

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 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

African (AFR) AF: 0.0434 AC: 1452 AN: 33474

American (AMR) AF: 0.0292 AC: 1305 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0713 AC: 1863 AN: 26134

East Asian (EAS) AF: 0.153 AC: 6068 AN: 39692

South Asian (SAS) AF: 0.122 AC: 10512 AN: 86248

European-Finnish (FIN) AF: 0.0569 AC: 3038 AN: 53420

Middle Eastern (MID) AF: 0.0622 AC: 359 AN: 5768

European-Non Finnish (NFE) AF: 0.0738 AC: 82013 AN: 1111700

Other (OTH) AF: 0.0784 AC: 4736 AN: 60388

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

African (AFR) AF: 0.0441 AC: 1833 AN: 41560

American (AMR) AF: 0.0366 AC: 559 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3470

East Asian (EAS) AF: 0.174 AC: 902 AN: 5184

South Asian (SAS) AF: 0.123 AC: 594 AN: 4818

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10612

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0726 AC: 4935 AN: 68008

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0693 Hom.: 1040

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

Sep 25, 2009

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Dec 10, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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 v4.9

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
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.31
Sift	Benign	0.094	T
Sift4G	Benign	0.12	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
Mutation Taster		=43/57	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs1127354; hg19: chr20-3193842; COSMIC: COSV66318275; COSMIC: COSV66318275;