rs1555773628

Variant names:

• chr20-3213359-G-C
• rs1555773628
• NM_033453.4:c.165G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033453.4(ITPA):​c.165G>C​(p.Gln55His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33920488).

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.165G>C	p.Gln55His	missense	Exon 3 of 8	NP_258412.1	A0A0S2Z3W7
	ITPA	NM_001424408.1		c.165G>C	p.Gln55His	missense	Exon 3 of 9	NP_001411337.1
	ITPA	NM_001424409.1		c.291G>C	p.Gln97His	missense	Exon 4 of 9	NP_001411338.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.165G>C	p.Gln55His	missense	Exon 3 of 8	ENSP00000369456.3	Q9BY32-1
	ITPA	ENST00000455664.6	TSL:1	c.114G>C	p.Gln38His	missense	Exon 3 of 8	ENSP00000413282.1	Q9BY32-2
	ITPA	ENST00000399838.3	TSL:1	c.67-626G>C		intron	N/A	ENSP00000382732.3	Q9BY32-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inosine triphosphatase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		3.4
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Benign	0.16	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.48
MutPred		0.49		Loss of disorder (P = 0.1496)
MVP		0.40
MPC		0.27
ClinPred		0.70	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.57
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1555773628; hg19: chr20-3194005;