rs7270101

Variant names:

• chr20-3213247-A-C
• rs7270101
• NM_033453.4:c.124+21A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-3213247-A-C
• chr20-3213247-A-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.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
• Publications: 177 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 (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	NM_033453.4	MANE Select	c.124+21A>C		intron	N/A	NP_258412.1	A0A0S2Z3W7
	ITPA	NM_001424408.1		c.124+21A>C		intron	N/A	NP_001411337.1
	ITPA	NM_001424409.1		c.250+21A>C		intron	N/A	NP_001411338.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.124+21A>C		intron	N/A	ENSP00000369456.3	Q9BY32-1
	ITPA	ENST00000455664.6	TSL:1	c.73+21A>C		intron	N/A	ENSP00000413282.1	Q9BY32-2
	ITPA	ENST00000399838.3	TSL:1	c.67-738A>C		intron	N/A	ENSP00000382732.3	Q9BY32-3

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

GnomAD2 exomes AF: 0.0873 AC: 21964 AN: 251474 AF XY: 0.0866

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 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

African (AFR) AF: 0.0732 AC: 2452 AN: 33480

American (AMR) AF: 0.0729 AC: 3260 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 2042 AN: 26134

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0308 AC: 2657 AN: 86258

European-Finnish (FIN) AF: 0.0780 AC: 4166 AN: 53420

Middle Eastern (MID) AF: 0.0815 AC: 470 AN: 5768

European-Non Finnish (NFE) AF: 0.135 AC: 150519 AN: 1111908

Other (OTH) AF: 0.103 AC: 6233 AN: 60392

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

African (AFR) AF: 0.0727 AC: 3018 AN: 41528

American (AMR) AF: 0.0924 AC: 1412 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0806 AC: 280 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4822

European-Finnish (FIN) AF: 0.0645 AC: 684 AN: 10598

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8806 AN: 67990

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.113 Hom.: 1662

Bravo AF: 0.0980

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 35 (1)
-	-	1	Inosine triphosphatase deficiency (2)
-	-	1	not provided (1)
-	-	-	peginterferon alfa-2b and ribavirin response - Toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.75
PhyloP100		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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