NM_033453.4:c.41C>T

Variant names:

• chr20-3209592-C-T
• NM_033453.4:c.41C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033453.4(ITPA):​c.41C>T​(p.Thr14Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T14T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033453.4. 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_033453.4	MANE Select	c.41C>T	p.Thr14Met	missense	Exon 1 of 8	NP_258412.1	A0A0S2Z3W7
	ITPA	NM_001324236.2		c.-300C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001311165.1	Q8WWI0
	ITPA	NM_001424408.1		c.41C>T	p.Thr14Met	missense	Exon 1 of 9	NP_001411337.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.41C>T	p.Thr14Met	missense	Exon 1 of 8	ENSP00000369456.3	Q9BY32-1
	ITPA	ENST00000399838.3	TSL:1	c.41C>T	p.Thr14Met	missense	Exon 1 of 6	ENSP00000382732.3	Q9BY32-3
	ITPA	ENST00000455664.6	TSL:1	c.15+26C>T		intron	N/A	ENSP00000413282.1	Q9BY32-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		5.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Gain of MoRF binding (P = 0.0615)
MVP		0.81
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.61
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

hg19: chr20-3190238;