NPM1

protein-coding

nucleophosmin 1

Gene summary

The protein encoded by this gene is involved in several cellular processes, including centrosome duplication, protein chaperoning, and cell proliferation. The encoded phosphoprotein shuttles between the nucleolus, nucleus, and cytoplasm, chaperoning ribosomal proteins and core histones from the nucleus to the cytoplasm. This protein is also known to sequester the tumor suppressor ARF in the nucleolus, protecting it from degradation until it is needed. Mutations in this gene are associated with acute myeloid leukemia. Dozens of pseudogenes of this gene have been identified. [provided by RefSeq, Aug 2017]

MANE transcript

NM_002520.7

Inheritance

ClinVar variants

P:7U:20B:12

Top phenotype

dyskeratosis congenita

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:171,387,116-171,411,810

External References & Databases

Ensembl (ENSG00000181163)

Transcript & Mutation Effects

hg38 • Region Span ~24.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dyskeratosis congenitaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: PanelApp Australia

dyskeratosis congenitaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: G2P

dyskeratosis congenitaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015780

Submitter: Orphanet

bone marrow failure syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000159

Submitter: ClinGen

NPM1 was first reported in relation to autosomal dominant bone marrow failure syndrome in 2019 (Nachmani et al., PMID: 31570891). Variants in NPM1 have been identified in individuals reported as having classic dyskeratosis congenita. However, due to the lack of association between NPM1 and telomere maintenance function, we determined that the syndrome described in Nachmani et al. is best described as bone marrow failure syndrome. As there are no other reported disease associations with NPM1 variants, no lumping and splitting was needed for this curation. Two variants (missense and an in-frame deletion) that have been reported in two probands in one publication (PMID:31570891) are included in this curation. These variants were observed in individuals with bone marrow failure with additional features including skin pigmentation abnormalities, nail dystrophy, thrombocytopenia, growth defects and skeletal abnormalities; telomere length was not reported. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, in vitro functional assays including cell line rescue and biochemical function evidence (PMID: 31570891). In summary, there is limited evidence supporting the relationship between NPM1 and autosomal dominant bone marrow failure syndrome. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Childhood, Adolescent, and Young Adult Cancer Predisposition GCEP on the meeting date April 8, 2025 (SOP Version 11).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NPM1 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 16

not providedTotal: 12

NPM1-related disorderTotal: 12

Acute myeloid leukemiaTotal: 10

Acute myeloid leukemia with multilineage dysplasiaTotal: 1

Bone marrow failure syndromeTotal: 1

Myelodysplastic syndrome progressed to acute myeloid leukemiaTotal: 1

Dyskeratosis congenitaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002520.7. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				10 clinvar	1 clinvar	11
missense			13 clinvar	1 clinvar		14
nonsense			2 clinvar			2
start loss						0
frameshift	7 clinvar		2 clinvar			9
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	7	0	20	11	1	39

Highest pathogenic variant AF is 0.000017140286

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 126 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002520.7	RefSeq	NP_002511.1	11	MANE Select
ENST00000296930.10	Ensembl	ENSP00000296930.5	11	MANE Select
NM_001037738.3	RefSeq	NP_001032827.1	10	Standard
NM_001355006.2	RefSeq	NP_001341935.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
npm1b	Danio rerio	Structure: myeloid cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

npm1b

Danio rerio

Structure: myeloid cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Disease
Gene expression (Transcription)
Generic Transcription Pathway
Interactions of Rev with host cellular proteins
Host Interactions of HIV factors

Biological Process

ribosomal large subunit export from nucleus
ribosomal small subunit export from nucleus
DNA repair
nucleosome assembly
chromatin remodeling

Molecular Function

core promoter binding
chromatin binding
transcription coactivator activity
RNA binding
protein kinase inhibitor activity

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296930
Coding exons: 11
Length: 24022
Individuals with no LoFs: 124610
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124612
p: 0.00000802

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.95	84	152	0.554	0.00000720	1959
Missense (PolyPhen)		3	20.679	0.14507		355
Synonymous	-1.84	67	50.4	1.33	0.00000251	489
Loss of Function	3.97	0	18.4	0.00	8.74e-7	243

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000055	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000010	0.0000089	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Binds ribosome presumably to drive ribosome nuclear export. Associated with nucleolar ribonucleoprotein structures and bind single-stranded nucleic acids. Acts as a chaperonin for the core histones H3, H2B and H4. Stimulates APEX1 endonuclease activity on apurinic/apyrimidinic (AP) double- stranded DNA but inhibits APEX1 endonuclease activity on AP single-stranded RNA. May exert a control of APEX1 endonuclease activity within nucleoli devoted to repair AP on rDNA and the removal of oxidized rRNA molecules. In concert with BRCA2, regulates centrosome duplication. Regulates centriole duplication: phosphorylation by PLK2 is able to trigger centriole replication. Negatively regulates the activation of EIF2AK2/PKR and suppresses apoptosis through inhibition of EIF2AK2/PKR autophosphorylation. Antagonizes the inhibitory effect of ATF5 on cell proliferation and relieves ATF5-induced G2/M blockade (PubMed:22528486). In complex with MYC enhances the transcription of MYC target genes (PubMed:25956029). {ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:16107701, ECO:0000269|PubMed:17015463, ECO:0000269|PubMed:18809582, ECO:0000269|PubMed:19188445, ECO:0000269|PubMed:20352051, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:22002061, ECO:0000269|PubMed:22528486, ECO:0000269|PubMed:25956029}.;
Disease: DISEASE: Note=A chromosomal aberration involving NPM1 is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with ALK. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. {ECO:0000269|PubMed:8122112, ECO:0000269|PubMed:8633037}.; DISEASE: Note=A chromosomal aberration involving NPM1 is found in a form of acute promyelocytic leukemia. Translocation t(5;17)(q32;q11) with RARA. {ECO:0000269|PubMed:8562957}.; DISEASE: Note=A chromosomal aberration involving NPM1 is a cause of myelodysplastic syndrome (MDS). Translocation t(3;5)(q25.1;q34) with MLF1. {ECO:0000269|PubMed:8570204}.; DISEASE: Note=Defects in NPM1 are associated with acute myelogenous leukemia (AML). Mutations in exon 12 affecting the C- terminus of the protein are associated with an aberrant cytoplasmic location. {ECO:0000269|PubMed:15659725}.;

Recessive Scores

pRec: 0.579

Intolerance Scores

LoFtool: 0.523
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.962

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium