rs150904363

chr20-3214028-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033453.4(ITPA):c.233A>G(p.Asn78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,614,174 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N78I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (8 hom.)
• Consequence: ITPA NM_033453.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012376815).
• BP6: Variant 20-3214028-A-G is Benign according to our data. Variant chr20-3214028-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 464829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152286) while in subpopulation SAS AF= 0.000622 (3/4826). AF 95% confidence interval is 0.000457. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPA	NM_033453.4	c.233A>G	p.Asn78Ser	missense_variant	4/8	ENST00000380113.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPA	ENST00000380113.8	c.233A>G	p.Asn78Ser	missense_variant	4/8	1	NM_033453.4	P1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00132 AC: 331 AN: 251478 Hom.: 4 AF XY: 0.00130 AC XY: 177 AN XY: 135914

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000796 AC: 1163 AN: 1461888 Hom.: 8 Cov.: 31 AF XY: 0.000820 AC XY: 596 AN XY: 727246

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0190

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74454

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00149 Hom.: 6

Bravo AF: 0.000873

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00104

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2018

- -

Inosine triphosphatase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

ITPA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Benign	0.078
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.16
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.031	D;D;T
Polyphen		0.016	B;.;.
Vest4		0.23
MVP		0.55
MPC		0.24
ClinPred		0.046	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs150904363; hg19: chr20-3194674;