Hemolytic anemia due to pyrimidine 5' nucleotidase deficiency

Summary

Hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency (MONDO:0009946) is a disease caused by NT5C3A (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NT5C3A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 58

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency
Mondo ID	MONDO:0009946
MeSH	C564859
OMIM	266120
Orphanet	35120
DOID	DOID:0051007
UMLS	C1849507
MedGen	341470
GARD	0016635
Is cancer (heuristic)	no

Also known as: anemia, congenital, nonspherocytic hemolytic, 8 · anemia, hemolytic, due to UMPH1 deficiency · hemolytic anaemia due to P5N deficiency · hemolytic anaemia due to UMPH1 deficiency · hemolytic anemia due to P5N deficiency · hemolytic anemia due to UMPH1 deficiency · P5N deficiency · pyrimidine 5-prime nucleotidase deficiency, hemolytic anaemia due to · pyrimidine 5-prime nucleotidase deficiency, hemolytic anemia due to · UMPH1 deficiency · uridine 5’-monophosphate hydrolase deficiency · uridine 5-prime monophosphate hydrolase deficiency, hemolytic anaemia due to · uridine 5-prime monophosphate hydrolase deficiency, hemolytic anemia due to

Data availability: 58 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency

Related subtypes (9): anemia, nonspherocytic hemolytic, gamma-glutamylcysteine synthetase deficiency, glutathione synthetase deficiency without 5-oxoprolinuria, non-spherocytic hemolytic anemia due to hexokinase deficiency, pyruvate kinase deficiency of red cells, hemolytic anemia due to adenylate kinase deficiency, hemolytic anemia due to glucophosphate isomerase deficiency, hemolytic anemia due to glutathione reductase deficiency, hemolytic anemia due to erythrocyte adenosine deaminase overproduction

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

58 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 11 pathogenic, 6 likely benign, 5 benign, 3 benign/likely benign, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687500	NM_001002010.5(NT5C3A):c.718G>T (p.Glu240Ter)	NT5C3A	Pathogenic	criteria provided, single submitter
4479	NM_001002010.5(NT5C3A):c.395A>T (p.Asp132Val)	NT5C3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4480	NM_001002010.5(NT5C3A):c.631C>T (p.Gln211Ter)	NT5C3A	Pathogenic	criteria provided, single submitter
4481	NM_001002010.5(NT5C3A):c.694-1G>T	NT5C3A	Pathogenic	no assertion criteria provided
4482	NM_001002010.5(NT5C3A):c.844_845dup (p.Val283fs)	NT5C3A	Pathogenic	criteria provided, single submitter
4483	NM_001002010.5(NT5C3A):c.645T>G (p.Tyr215Ter)	NT5C3A	Pathogenic	no assertion criteria provided
4484	NM_001002010.5(NT5C3A):c.486dup (p.Ala163fs)	NT5C3A	Pathogenic	no assertion criteria provided
4485	NM_001002010.5(NT5C3A):c.694-1G>C	NT5C3A	Pathogenic	no assertion criteria provided
4486	NM_001002010.5(NT5C3A):c.671A>G (p.Asn224Ser)	NT5C3A	Pathogenic	no assertion criteria provided
4487	NM_001002010.5(NT5C3A):c.679del (p.Asp227fs)	NT5C3A	Pathogenic	no assertion criteria provided
4488	NM_001002010.5(NT5C3A):c.823G>C (p.Gly275Arg)	NT5C3A	Pathogenic	no assertion criteria provided
992939	NM_001002010.5(NT5C3A):c.166C>T (p.Arg56Ter)	NT5C3A	Pathogenic	criteria provided, single submitter
1299469	NM_001002010.5(NT5C3A):c.342dup (p.Cys115fs)	NT5C3A	Likely pathogenic	no assertion criteria provided
4081562	NM_001002010.5(NT5C3A):c.333del (p.Thr112fs)	NT5C3A	Likely pathogenic	criteria provided, single submitter
2434452	NM_001002010.5(NT5C3A):c.520G>A (p.Val174Ile)	NT5C3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3408138	NM_001002010.5(NT5C3A):c.43G>T (p.Ala15Ser)	NT5C3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1330398	NM_001002010.5(NT5C3A):c.577C>A (p.Pro193Thr)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330876	NM_001002010.5(NT5C3A):c.670A>C (p.Asn224His)	NT5C3A	Uncertain significance	criteria provided, single submitter
1500103	NM_001002010.5(NT5C3A):c.776A>G (p.Asn259Ser)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2070549	NM_001002010.5(NT5C3A):c.903G>C (p.Glu301Asp)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434449	NM_001002010.5(NT5C3A):c.599G>T (p.Gly200Val)	NT5C3A	Uncertain significance	criteria provided, single submitter
2434450	NM_001002010.5(NT5C3A):c.554A>G (p.Asp185Gly)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434451	NM_001002010.5(NT5C3A):c.430A>G (p.Met144Val)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434453	NM_001002010.5(NT5C3A):c.628C>T (p.Arg210Cys)	NT5C3A	Uncertain significance	criteria provided, single submitter
2434454	NM_001002010.5(NT5C3A):c.809T>C (p.Leu270Pro)	NT5C3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2689620	NM_001002010.5(NT5C3A):c.254A>T (p.Asp85Val)	NT5C3A	Uncertain significance	criteria provided, single submitter
2689621	NM_001002010.5(NT5C3A):c.544A>C (p.Asn182His)	NT5C3A	Uncertain significance	criteria provided, single submitter
2689622	NM_001002010.5(NT5C3A):c.921_953dup (p.Glu318_Ser319insAspSerTyrAspIleValLeuValGlnAspGlu)	NT5C3A	Uncertain significance	criteria provided, single submitter
2689623	NM_001002010.5(NT5C3A):c.607G>A (p.Asp203Asn)	NT5C3A	Uncertain significance	criteria provided, single submitter
2689624	NM_001002010.5(NT5C3A):c.362A>C (p.Gln121Pro)	NT5C3A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NT5C3A	Definitive	Autosomal recessive	hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NT5C3A	Orphanet:35120	Hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NT5C3A	HGNC:17820	ENSG00000122643	Q9H0P0	Cytosolic 5’-nucleotidase 3A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NT5C3A	Cytosolic 5’-nucleotidase 3A	Nucleotidase which shows specific activity towards cytidine monophosphate (CMP) and 7-methylguanosine monophosphate (m(7)GMP).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NT5C3A	Enzyme (other)	yes	3.1.3.91	Pyrimidine_nucleotidase_eu, HAD_sf, HAD-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NT5C3A	138	ubiquitous	marker	quadriceps femoris, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NT5C3A	1,223

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NT5C3A	Q9H0P0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Pyrimidine catabolism	1	878.5×	0.001	NT5C3A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyrimidine nucleoside metabolic process	1	4213.0×	6e-04	NT5C3A
dTMP catabolic process	1	2808.7×	6e-04	NT5C3A
CMP catabolic process	1	2106.5×	6e-04	NT5C3A
UMP catabolic process	1	2106.5×	6e-04	NT5C3A
dCMP catabolic process	1	1872.4×	6e-04	NT5C3A
dUMP catabolic process	1	1872.4×	6e-04	NT5C3A
defense response to virus	1	69.3×	0.014	NT5C3A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NT5C3A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NT5C3A	3.1.3.91	7-methylguanosine nucleotidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NT5C3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NT5C3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.