NEMF

protein-coding

nuclear export mediator factor

Gene summary

This gene encodes a component of the ribosome quality control complex. The encoded protein facilitates the recognition and ubiquitination of stalled 60S subunits by the ubiquitin ligase listerin. A similar protein in fly functions as a tumor suppressor. [provided by RefSeq, Jul 2016]

Previous symbols:

SDCCAG1

MANE transcript

NM_004713.6

Inheritance

AD, AR

ClinVar variants

P:31U:158B:33

Top phenotype

Intellectual developmental disorder with speech delay and axonal peripheral neuropathy

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr14:49,782,083-49,852,821

External References & Databases

Ensembl (ENSG00000165525)

Transcript & Mutation Effects

hg38 • Region Span ~70.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with speech delay and axonal peripheral neuropathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030849

Submitter: PanelApp Australia

intellectual developmental disorder with speech delay and axonal peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030849

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with speech delay and axonal peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030849

Submitter: PanelApp Australia

intellectual developmental disorder with speech delay and axonal peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030849

Submitter: ClinGen

The NEMF gene is located on chromosome 14 at 14q21.3 and encodes the nuclear export mediator factor protein, which recognizes stalled ribosomes structures that have a nascent chain linked to the tRNA. Biallelic variants in NEMF were first reported in relation to autosomal recessive intellectual developmental disorder with speech delay and axonal peripheral neuropathy in 2020 (Martin et al., PMID: 32934225). Affected individuals typically present with developmental delay with speech delay, axonal neuropathy, ataxia, distal muscle atrophy, hypotonia, respiratory distress, abnormal brain imaging, and hand and foot deformities. Variants in this gene have been reported in at least 6 individuals from two publications, including 6 unique loss of function variants and 1 missense variant included in this curation. Variants in this gene segregated with disease in at least two families, including a LoD score of 4.5 in one large consanguineous family (PMID: 32934225; Ahmed et al., 2021, PMID: 33048237). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be biallelic loss of function. This gene-disease relationship is also supported by in vitro functional assays and mouse models which recapitulate the clinical phenotype. In summary, there is strong evidence to support the relationship between NEMF and autosomal recessive intellectual developmental disorder with speech delay and axonal peripheral neuropathy. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This strong classification was approved by the ClinGen Syndromic Disorders GCEP in the meeting on October 3, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Intellectual developmental disorder with speech delay and axonal peripheral neuropathyAR

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 32934225; 33048237

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NEMF variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 131

not providedTotal: 54

Intellectual developmental disorder with speech delay and axonal peripheral neuropathyTotal: 19

NEMF-related disorderTotal: 17

not specifiedTotal: 10

See casesTotal: 2

Prostate cancerTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004713.6. 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			3 clinvar	24 clinvar	3 clinvar	30
missense		1 clinvar	142 clinvar	6 clinvar		149
nonsense	6 clinvar	2 clinvar				8
start loss	1 clinvar		1 clinvar			2
frameshift	12 clinvar	6 clinvar	3 clinvar			21
splice donor/acceptor (+/-2bp)		3 clinvar	9 clinvar			12
Total	19	12	158	30	3	222

Highest pathogenic variant AF is 0.00003185988

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004713.6	RefSeq	NP_004704.3	33	MANE Select
ENST00000298310.10	Ensembl	ENSP00000298310.5	33	MANE Select
NM_001301732.3	RefSeq	NP_001288661.2	32	Standard
ENST00000554626.5	Ensembl	ENSP00000451740.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

nuclear export
rescue of stalled ribosome
ribosome-associated ubiquitin-dependent protein catabolic process

Molecular Function

tRNA binding
ribosomal large subunit binding

Cellular Component

nucleus
RQC complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000298310
Coding exons: 33
Length: 69925
Individuals with no LoFs: 125689
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125748
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	470	548	0.857	0.0000267	7131
Missense (PolyPhen)		136	204.64	0.66459		2693
Synonymous	-1.13	202	183	1.11	0.00000924	1863
Loss of Function	5.63	21	72.9	0.288	0.00000399	900

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00018	0.00016	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the ribosome quality control complex (RQC), a ribosome-associated complex that mediates ubiquitination and extraction of incompletely synthesized nascent chains for proteasomal degradation. NEMF is responsible for selective recognition of stalled 60S subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety. NEMF is important for the stable association of LTN1 to the complex (PubMed:25578875). May indirectly play a role in nuclear export (PubMed:16103875). {ECO:0000269|PubMed:16103875, ECO:0000269|PubMed:25578875}.;

Intolerance Scores

RVIS EVS: -1.7
RVIS percentile EVS: 2.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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