20-3209393-C-G

Variant names:

• chr20-3209393-C-G
• rs45620433
• ENST00000932180.1:c.-159C>G

Variant summary

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

The NM_001424409.1(ITPA):​c.192+681C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 739,010 control chromosomes in the GnomAD database, including 20,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3435 hom., cov: 32)
  • Exomes 𝑓: 0.23 (17353 hom.)
• Consequence: ITPA NM_001424409.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.54
• 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

ENSG00000289494 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-3209393-C-G is Benign according to our data. Variant chr20-3209393-C-G is described in ClinVar as Benign. ClinVar VariationId is 1251484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424409.1. 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_001424409.1		c.192+681C>G		intron	N/A	NP_001411338.1
	ITPA	NM_001324237.2		c.-272+360C>G		intron	N/A	NP_001311166.1	Q8WWI0
	ITPA	NM_001324238.2		c.-275+360C>G		intron	N/A	NP_001311167.1	Q8WWI0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000932180.1		c.-159C>G		5_prime_UTR	Exon 1 of 6	ENSP00000602239.1
	ENSG00000289494	ENST00000690923.3		n.86G>C		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000289494	ENST00000795319.1		n.66G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31203 AN: 151974 Hom.: 3428 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.233 AC: 136605 AN: 586918 Hom.: 17353 Cov.: 7 AF XY: 0.241 AC XY: 75832 AN XY: 314606

African (AFR) AF: 0.160 AC: 2593 AN: 16168

American (AMR) AF: 0.228 AC: 7806 AN: 34260

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 4173 AN: 19882

East Asian (EAS) AF: 0.317 AC: 10101 AN: 31834

South Asian (SAS) AF: 0.375 AC: 23416 AN: 62436

European-Finnish (FIN) AF: 0.143 AC: 5759 AN: 40246

Middle Eastern (MID) AF: 0.290 AC: 932 AN: 3212

European-Non Finnish (NFE) AF: 0.215 AC: 74801 AN: 347520

Other (OTH) AF: 0.224 AC: 7024 AN: 31360

GnomAD4 genome AF: 0.205 AC: 31235 AN: 152092 Hom.: 3435 Cov.: 32 AF XY: 0.205 AC XY: 15239 AN XY: 74328

African (AFR) AF: 0.162 AC: 6724 AN: 41516

American (AMR) AF: 0.208 AC: 3173 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1545 AN: 5148

South Asian (SAS) AF: 0.386 AC: 1853 AN: 4804

European-Finnish (FIN) AF: 0.142 AC: 1506 AN: 10602

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14777 AN: 67962

Other (OTH) AF: 0.236 AC: 499 AN: 2110

Alfa AF: 0.198 Hom.: 395

Bravo AF: 0.206

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.54
PhyloP100		-1.5
PromoterAI		-0.045	Neutral
Mutation Taster		=300/0	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: rs45620433; hg19: chr20-3190039;