20-3219057-G-A

Variant names:

• chr20-3219057-G-A
• rs2422862
• ENST00000609835.5:n.890G>A

Variant summary

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

The ENST00000609835.5(ITPA):​n.890G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 209,088 control chromosomes in the GnomAD database, including 82,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (61057 hom., cov: 30)
  • Exomes 𝑓: 0.87 (21654 hom.)
• Consequence: ITPA ENST00000609835.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.823
• Publications: 5 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=-0.87).
• BP6: Variant 20-3219057-G-A is Benign according to our data. Variant chr20-3219057-G-A is described in ClinVar as Benign. ClinVar VariationId is 3256808.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000609835.5. 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.411+425G>A		intron	N/A	NP_258412.1
	ITPA	NM_001424408.1		c.411+425G>A		intron	N/A	NP_001411337.1
	ITPA	NM_001424409.1		c.537+425G>A		intron	N/A	NP_001411338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000609835.5	TSL:1	n.890G>A		non_coding_transcript_exon	Exon 5 of 5
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.411+425G>A		intron	N/A	ENSP00000369456.3
	ITPA	ENST00000455664.6	TSL:1	c.360+425G>A		intron	N/A	ENSP00000413282.1

Frequencies

GnomAD3 genomes AF: 0.894 AC: 135869 AN: 151924 Hom.: 60993 Cov.: 30

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.919

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.903

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.758

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.893

GnomAD4 exome AF: 0.868 AC: 49541 AN: 57046 Hom.: 21654 Cov.: 0 AF XY: 0.870 AC XY: 26314 AN XY: 30232

African (AFR) AF: 0.956 AC: 799 AN: 836

American (AMR) AF: 0.927 AC: 3192 AN: 3444

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 945 AN: 1170

East Asian (EAS) AF: 1.00 AC: 2706 AN: 2706

South Asian (SAS) AF: 0.885 AC: 8977 AN: 10144

European-Finnish (FIN) AF: 0.839 AC: 2418 AN: 2882

Middle Eastern (MID) AF: 0.853 AC: 133 AN: 156

European-Non Finnish (NFE) AF: 0.849 AC: 27769 AN: 32692

Other (OTH) AF: 0.863 AC: 2602 AN: 3016

GnomAD4 genome AF: 0.894 AC: 135994 AN: 152042 Hom.: 61057 Cov.: 30 AF XY: 0.895 AC XY: 66490 AN XY: 74310

African (AFR) AF: 0.961 AC: 39866 AN: 41480

American (AMR) AF: 0.919 AC: 14037 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2785 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5176 AN: 5184

South Asian (SAS) AF: 0.903 AC: 4362 AN: 4828

European-Finnish (FIN) AF: 0.829 AC: 8709 AN: 10510

Middle Eastern (MID) AF: 0.760 AC: 222 AN: 292

European-Non Finnish (NFE) AF: 0.855 AC: 58131 AN: 67990

Other (OTH) AF: 0.894 AC: 1885 AN: 2108

Alfa AF: 0.864 Hom.: 35243

Bravo AF: 0.902

Asia WGS AF: 0.954 AC: 3312 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.78
DANN	Benign	0.39
PhyloP100		-0.82
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: rs2422862; hg19: chr20-3199703;