Genetic Variant ITPA:c.-113C>T (chr20-3209439-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001424409.1(ITPA):c.192+727C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,043,096 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.017 ( 56 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 42 hom. )

Consequence

ITPA
NM_001424409.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.148

Publications

1 publications found

Variant links:

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

ITPA links:

ENSG00000289494 (HGNC:):

ENSG00000289494 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 20-3209439-C-T is Benign according to our data. Variant chr20-3209439-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264012.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424409.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
ITPA	NM_001424409.1	c.192+727C>T	intron	N/A	NP_001411338.1
ITPA	NM_001324237.2	c.-272+406C>T	intron	N/A	NP_001311166.1	Q8WWI0
ITPA	NM_001324238.2	c.-275+406C>T	intron	N/A	NP_001311167.1	Q8WWI0

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
ITPA	ENST00000932180.1	c.-113C>T	5_prime_UTR	Exon 1 of 6	ENSP00000602239.1
ENSG00000289494	ENST00000690923.3	n.40G>A	non_coding_transcript_exon	Exon 1 of 1
ENSG00000289494	ENST00000795319.1	n.20G>A	non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2580

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0585

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00747

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0129

GnomAD4 exome

AF:

0.00169

AC:

1502

AN:

890842

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

655

AN XY:

460424

show subpopulations

African (AFR)

AF:

0.0543

AC:

1191

AN:

21952

American (AMR)

AF:

0.00294

AC:

104

AN:

35340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22000

East Asian (EAS)

AF:

0.00

AC:

AN:

33714

South Asian (SAS)

AF:

0.0000575

AC:

AN:

69546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48182

Middle Eastern (MID)

AF:

0.00301

AC:

AN:

4650

European-Non Finnish (NFE)

AF:

0.0000717

AC:

AN:

613800

Other (OTH)

AF:

0.00348

AC:

145

AN:

41658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

152

229

305

381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0170

AC:

2581

AN:

152254

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1212

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0583

AC:

2424

AN:

41544

American (AMR)

AF:

0.00746

AC:

114

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68020

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

119

238

358

477

596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00960

Hom.:

Bravo

AF:

0.0195

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.3

(source)

DANN

Benign

0.85

PhyloP100

0.15

PromoterAI

0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over