NSMCE3

protein-coding

NSE3 homolog, SMC5-SMC6 complex component, the group of SMC5-6 protein complex|MAGE family

Gene summary

The protein encoded by this gene is part of the SMC5-6 chromatin reorganizing complex and is a member of the MAGE superfamily. This is an intronless gene. [provided by RefSeq, May 2011]

Previous symbols:

NDNL2

MANE transcript

NM_138704.4

Inheritance

ClinVar variants

P:2U:84B:105

Top phenotype

Lung disease, immunodeficiency, and chromosome breakage syndrome

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr15:29,264,989-29,269,822

External References & Databases

Ensembl (ENSG00000185115)

Transcript & Mutation Effects

hg38 • Region Span ~4.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lung disease, immunodeficiency, and chromosome breakage syndrome;LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014984

Submitter: ClinGen

Biallelic germline variants in NSMCE3 were first reported in relation to Lung disease, immunodeficiency and chromosome breakage syndrome in 2016 (PMID: 27427983). NSMCE3 is a component of the SMC5/6 complex, which has roles in maintenance of chromosome integrity and genomic stability. In the initial report, four patients from two families were identified due to severe lung disease following multiple virus-induced pneumonias. Further testing identified chromosomal breakage in cultured lymphocytes, as well as a combined T and B cell dysfunction with recurrent infections. Subsequent studies involving five patients with biallelic NSMCE3 missense variants did not reveal immunodeficiency; however, all presented with severe lung disease (PMID: 33741030). Based on this information, it is likely patients with biallelic variants in NSMCE3 display variable expressivity of immune defects. Functional studies demonstrate that the reported NSMCE3 variants destabilize the SMC5/6 complex, leading to a reduction in steady-state levels of its subunits and chromosomal instability. Experiments on patient-derived cells exhibit hypersensitivity to genotoxic stress and defects suggestive of impaired homologous recombination (HR) (PMID: 27427983). In particular, these cells show alterations in γ-H2AX recruitment following irradiation. Clinical testing of γ-H2AX recruitment following irradiation may be useful to support the findings of impaired DNA double-strand break repair seen in NSMCE3 deficencny. In summary, there is limited evidence to support the immunodeficiency component of this gene-disease relationship. This classification was approved by the ClinGen SCID-CID Working Group on 1/15/2026 (SOP Version 10.1).

lung disease, immunodeficiency, and chromosome breakage syndrome;MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014984

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Lung disease, immunodeficiency, and chromosome breakage syndromeAR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Pulmonary

Intervention: Allergy/Immunology/Infectious

Rationale: Individuals have been described with severe and early-onset infections, and early awareness may allow preventive measures and early and aggressive treatment of infections

Refs: 27427983

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSMCE3 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 190

not specifiedTotal: 16

NSMCE3-related disorderTotal: 6

Lung disease, immunodeficiency, and chromosome breakage syndrome;Total: 6

Lung damage, immunodeficiency and chromosome breakage syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138704.4. 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				96 clinvar	1 clinvar	97
missense	1 clinvar	1 clinvar	79 clinvar	4 clinvar	4 clinvar	89
nonsense			1 clinvar			1
start loss						0
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	1	1	84	100	5	191

Highest pathogenic variant AF is 0.00009850593

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138704.4	RefSeq	NP_619649.1	1	MANE Select
ENST00000332303.6	Ensembl	ENSP00000330694.4	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

SUMOylation of DNA damage response and repair proteins
Post-translational protein modification
SUMO E3 ligases SUMOylate target proteins
Metabolism of proteins
SUMOylation

Biological Process

DNA repair
DNA recombination
positive regulation of protein ubiquitination
cellular response to UV
regulation of growth

Molecular Function

protein binding
protein dimerization activity

Cellular Component

chromosome, telomeric region
nucleoplasm
cytoplasm
Smc5-Smc6 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000332303
Coding exons: 1
Length: 1681
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.334	174	162	1.07	0.00000741	1946
Missense (PolyPhen)		30	44.158	0.67938		572
Synonymous	-2.32	97	72.0	1.35	0.00000336	622
Loss of Function	1.51	3	7.45	0.403	3.30e-7	88

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination (PubMed:20864041, PubMed:27427983). The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). In vitro enhances ubiquitin ligase activity of NSMCE1. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex (PubMed:20864041). May be a growth suppressor that facilitates the entry of the cell into cell cycle arrest (By similarity). {ECO:0000250|UniProtKB:Q9CPR8, ECO:0000269|PubMed:20864041, ECO:0000269|PubMed:27427983}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

RVIS EVS: 0.51
RVIS percentile EVS: 80.01

Essentials

Essential (gene trap): N