20-3221844-C-T

Variant names:

• chr20-3221844-C-T
• rs1329748108
• NM_033453.4:c.415C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033453.4(ITPA):​c.415C>T​(p.Arg139Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPA	NM_033453.4	c.415C>T	p.Arg139Trp	missense_variant	Exon 7 of 8	ENST00000380113.8	NP_258412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPA	ENST00000380113.8	c.415C>T	p.Arg139Trp	missense_variant	Exon 7 of 8	1	NM_033453.4	ENSP00000369456.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250610 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000410 AC: 6 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111982

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inosine triphosphatase deficiency Uncertain:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 139 of the ITPA protein (p.Arg139Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ITPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 533416). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		2.2
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.49
MutPred		0.46		Loss of disorder (P = 0.0144);.;.;
MVP		0.62
MPC		0.94
ClinPred		0.93	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.49
gMVP		0.69
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1329748108; hg19: chr20-3202490; COSMIC: COSV101200058; COSMIC: COSV101200058;