Variant rs1407446171 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_033453.4(ITPA):c.359_366dup(p.Gly123SerfsTer104) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A119A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ITPA
NM_033453.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.588

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-3218578-A-ACTCAGCAC is Pathogenic according to our data. Variant chr20-3218578-A-ACTCAGCAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPA	NM_033453.4 linkuse as main transcript	c.359_366dup	p.Gly123SerfsTer104	frameshift_variant	6/8	ENST00000380113.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPA	ENST00000380113.8 linkuse as main transcript	c.359_366dup	p.Gly123SerfsTer104	frameshift_variant	6/8	1	NM_033453.4	P1	Q9BY32-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

250252

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 35

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 05, 2021	PVS1, PS3, PM2 -
Pathogenic, criteria provided, single submitter	research	TIDEX, University of British Columbia	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 35 (MIM#616647). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0600 - Variant affects part of the annotated Ham1 family domain (DECIPHER). (I) 0704 - Another protein elongation variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This variant has been reported twice as likely pathogenic and pathogenic, while other elongations found further downstream have been reported as VUS (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in compound heterozygous and homozygous individuals with early-infantile epileptic encephalopathy, atypical cerebral palsy or myotonic seizures with microcephaly and global developmental delay (ClinVar, PMID: 26224535, PMID: 30542205, PMID: 34989426). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Fibroblasts from a homozygous individual had only 2.9% residual enzyme activity (PMID: 26224535). (SP) 1201 - Heterozygous variant detected in trans with a likely pathogenic heterozygous variant (p.(Asp109Tyr)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ITPA: PVS1, PM2, PM3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	The c.359_366dupTCAGCAC variant in the ITPA gene has been reported previously, in the homozygous state, in an individual with early onset encephalopathy who had 2.9% residual ITPA enzyme activity compared to wild type controls (Kevelam et al., 2015). This variant was also reported in the heterozygous state in a healthy individual who had 30% residual ITPA enzyme activity compared to wild type controls (Atanasova et al., 2007). The c.359_366dupTCAGCAC variant causes a frameshift starting with codon Glycine 123, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 104 of the new reading frame, denoted p.Gly123SerfsX104. This variant is predicted to cause loss of normal protein function as the last 72 amino acids are lost and replaced with 103 incorrect amino acids. The c.359_366dupTCAGCAC variant is observed in 6/125,736 (0.005%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). -

Partial congenital absence of teeth

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

Inosine triphosphatase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change results in a frameshift in the ITPA gene (p.Gly123Serfs*104). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acid(s) of the ITPA protein and extend the protein by 31 additional amino acid residues. This variant is present in population databases (rs763029259, gnomAD 0.01%). This frameshift has been observed in individual(s) with ITPA-related conditions (PMID: 26224535). ClinVar contains an entry for this variant (Variation ID: 218091). This variant disrupts a region of the ITPA protein in which other variant(s) (p.Trp151*) have been determined to be pathogenic (PMID: 26224535, 30856165). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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