20-3209556-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033453.4(ITPA):c.5C>A(p.Ala2Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity ITPA_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPA	NM_033453.4	c.5C>A	p.Ala2Glu	missense_variant	1/8	ENST00000380113.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPA	ENST00000380113.8	c.5C>A	p.Ala2Glu	missense_variant	1/8	1	NM_033453.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251014 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461630 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inosine triphosphatase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ITPA-related conditions. This variant is present in population databases (rs150370229, ExAC 0.02%). This sequence change replaces alanine with glutamic acid at codon 2 of the ITPA protein (p.Ala2Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;T;D
Sift4G	Uncertain	0.039	D;D;T
Polyphen		1.0	D;.;.
Vest4		0.49
MutPred		0.19		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);
MVP		0.74
MPC		1.1
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150370229; hg19: chr20-3190202;