rs67002563

Variant names:

• chr20-3213527-G-A
• rs67002563
• NM_033453.4:c.189+144G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_033453.4(ITPA):​c.189+144G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 966,216 control chromosomes in the GnomAD database, including 3,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (431 hom., cov: 32)
  • Exomes 𝑓: 0.074 (2674 hom.)
• Consequence: ITPA NM_033453.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.527
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-3213527-G-A is Benign according to our data. Variant chr20-3213527-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPA	NM_033453.4	c.189+144G>A		intron_variant	Intron 3 of 7	ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8	c.189+144G>A		intron_variant	Intron 3 of 7	1	NM_033453.4	ENSP00000369456.3

Frequencies

GnomAD3 genomes AF: 0.0682 AC: 10358 AN: 151950 Hom.: 433 Cov.: 32

Gnomad AFR AF: 0.0575

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0725

Gnomad OTH AF: 0.0623

GnomAD4 exome AF: 0.0735 AC: 59855 AN: 814148 Hom.: 2674 AF XY: 0.0764 AC XY: 32346 AN XY: 423376

African (AFR) AF: 0.0536 AC: 1086 AN: 20258

American (AMR) AF: 0.0307 AC: 1052 AN: 34306

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 1482 AN: 21164

East Asian (EAS) AF: 0.150 AC: 4981 AN: 33240

South Asian (SAS) AF: 0.123 AC: 8268 AN: 67022

European-Finnish (FIN) AF: 0.0583 AC: 2125 AN: 36450

Middle Eastern (MID) AF: 0.0692 AC: 204 AN: 2946

European-Non Finnish (NFE) AF: 0.0673 AC: 37685 AN: 559768

Other (OTH) AF: 0.0762 AC: 2972 AN: 38994

GnomAD4 genome AF: 0.0681 AC: 10354 AN: 152068 Hom.: 431 Cov.: 32 AF XY: 0.0683 AC XY: 5078 AN XY: 74314

African (AFR) AF: 0.0573 AC: 2378 AN: 41484

American (AMR) AF: 0.0386 AC: 590 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3468

East Asian (EAS) AF: 0.172 AC: 887 AN: 5154

South Asian (SAS) AF: 0.126 AC: 608 AN: 4812

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0725 AC: 4930 AN: 67972

Other (OTH) AF: 0.0611 AC: 129 AN: 2110

Alfa AF: 0.0688 Hom.: 54

Bravo AF: 0.0656

Asia WGS AF: 0.106 AC: 369 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

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	-0.80
CADD	Benign	6.9
DANN	Benign	0.83
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs67002563; hg19: chr20-3194173;