20-3213196-C-G

Variant names:

• chr20-3213196-C-G
• rs1127354
• NM_033453.4:c.94C>G

Variant summary

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

The NM_001324237.2(ITPA):​c.-244C>G variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPA NM_001324237.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• Publications: 358 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001324237.2. 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.94C>G	p.Pro32Ala	missense	Exon 2 of 8	NP_258412.1	A0A0S2Z3W7
	ITPA	NM_001324237.2		c.-244C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	NP_001311166.1	Q8WWI0
	ITPA	NM_001424408.1		c.94C>G	p.Pro32Ala	missense	Exon 2 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.94C>G	p.Pro32Ala	missense	Exon 2 of 8	ENSP00000369456.3	Q9BY32-1
	ITPA	ENST00000455664.6	TSL:1	c.43C>G	p.Pro15Ala	missense	Exon 2 of 8	ENSP00000413282.1	Q9BY32-2
	ITPA	ENST00000399838.3	TSL:1	c.67-789C>G		intron	N/A	ENSP00000382732.3	Q9BY32-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.29
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.0010	B
Vest4		0.61
MutPred		0.55		Loss of helix (P = 0.0626)
MVP		0.75
MPC		0.31
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.52
gMVP		0.58
Mutation Taster		=47/53	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

dbSNP: rs1127354; hg19: chr20-3193842;