rs2236206

Variant names:

• chr20-3223304-T-A
• rs2236206
• NM_033453.4:c.489-62T>A

Your query was ambiguous. Multiple possible variants found:

• chr20-3223304-T-A
• chr20-3223304-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033453.4(ITPA):​c.489-62T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 1,206,226 control chromosomes in the GnomAD database, including 200,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23849 hom., cov: 32)
  • Exomes 𝑓: 0.57 (176201 hom.)
• Consequence: ITPA NM_033453.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.42
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-3223304-T-A is Benign according to our data. Variant chr20-3223304-T-A is described in ClinVar as Benign. ClinVar VariationId is 1290702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPA	NM_033453.4	c.489-62T>A		intron_variant	Intron 7 of 7	ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8	c.489-62T>A		intron_variant	Intron 7 of 7	1	NM_033453.4	ENSP00000369456.3

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84425 AN: 151824 Hom.: 23827 Cov.: 32

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.606

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.577

GnomAD4 exome AF: 0.575 AC: 606038 AN: 1054288 Hom.: 176201 AF XY: 0.577 AC XY: 310895 AN XY: 538518

African (AFR) AF: 0.545 AC: 13926 AN: 25532

American (AMR) AF: 0.443 AC: 17438 AN: 39388

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 12570 AN: 23344

East Asian (EAS) AF: 0.612 AC: 22155 AN: 36176

South Asian (SAS) AF: 0.637 AC: 47591 AN: 74734

European-Finnish (FIN) AF: 0.462 AC: 21936 AN: 47480

Middle Eastern (MID) AF: 0.553 AC: 2787 AN: 5044

European-Non Finnish (NFE) AF: 0.583 AC: 440625 AN: 755508

Other (OTH) AF: 0.574 AC: 27010 AN: 47082

GnomAD4 genome AF: 0.556 AC: 84488 AN: 151938 Hom.: 23849 Cov.: 32 AF XY: 0.549 AC XY: 40785 AN XY: 74288

African (AFR) AF: 0.546 AC: 22621 AN: 41416

American (AMR) AF: 0.487 AC: 7439 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1874 AN: 3470

East Asian (EAS) AF: 0.606 AC: 3118 AN: 5146

South Asian (SAS) AF: 0.645 AC: 3107 AN: 4818

European-Finnish (FIN) AF: 0.435 AC: 4597 AN: 10556

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39767 AN: 67944

Other (OTH) AF: 0.579 AC: 1220 AN: 2108

Alfa AF: 0.558 Hom.: 2882

Bravo AF: 0.553

Asia WGS AF: 0.645 AC: 2242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 60. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.98
DANN	Benign	0.59
PhyloP100		-1.4
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: rs2236206; hg19: chr20-3203950;