rs34982958

Positions:

• chr20-3215295-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033453.4(ITPA):​c.278A>G​(p.Glu93Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,920 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (10 hom.)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.77

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008969754).
• BP6: Variant 20-3215295-A-G is Benign according to our data. Variant chr20-3215295-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00579 (881/152242) while in subpopulation AFR AF= 0.0202 (838/41538). AF 95% confidence interval is 0.019. There are 7 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPA	NM_033453.4	c.278A>G	p.Glu93Gly	missense_variant	5/8	ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8	c.278A>G	p.Glu93Gly	missense_variant	5/8	1	NM_033453.4	ENSP00000369456.3

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152124 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00146 AC: 366 AN: 251454 Hom.: 4 AF XY: 0.000979 AC XY: 133 AN XY: 135904

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000560 AC: 819 AN: 1461678 Hom.: 10 Cov.: 30 AF XY: 0.000506 AC XY: 368 AN XY: 727160

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00579 AC: 881 AN: 152242 Hom.: 7 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74424

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00136 Hom.: 3

Bravo AF: 0.00655

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2020

- -

Inosine triphosphatase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inosine triphosphatase deficiency;C4225256:Developmental and epileptic encephalopathy, 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Benign	-0.043
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.68	N;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.029	D;D;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.29
MVP		0.48
MPC		0.34
ClinPred		0.035	T
GERP RS		4.7
Varity_R		0.46
gMVP		0.57

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: rs34982958; hg19: chr20-3195941;