rs6139034

Positions:

• chr20-3221423-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_033453.4(ITPA):​c.412-418C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,068 control chromosomes in the GnomAD database, including 4,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (4128 hom., cov: 32)
• Consequence: ITPA NM_033453.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.430

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-3221423-C-T is Benign according to our data. Variant chr20-3221423-C-T is described in ClinVar as [Benign]. Clinvar id is 3256814.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPA	NM_033453.4	c.412-418C>T		intron_variant		ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8	c.412-418C>T		intron_variant		1	NM_033453.4	ENSP00000369456	P1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31967 AN: 151950 Hom.: 4127 Cov.: 32

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.231

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 31965 AN: 152068 Hom.: 4128 Cov.: 32 AF XY: 0.213 AC XY: 15859 AN XY: 74326

Gnomad4 AFR AF: 0.0923

Gnomad4 AMR AF: 0.204

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.235

Alfa AF: 0.243 Hom.: 6177

Bravo AF: 0.201

Asia WGS AF: 0.488 AC: 1695 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 37% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 34. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.8
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs6139034; hg19: chr20-3202069;