GeneBe

NSMF

protein-coding

NMDA receptor synaptonuclear signaling and neuronal migration factor, the group of MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is involved in guidance of olfactory axon projections and migration of luteinizing hormone-releasing hormone neurons. Defects in this gene are a cause of idiopathic hypogonadotropic hypogonadism (IHH). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

Previous symbols:
  • NELF

MANE transcript

NM_001130969.3

Inheritance

AD

ClinVar variants

P:2U:117B:53

Top phenotype

Hypogonadotropic hypogonadism 9 with or without anosmia

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr9:137,447,570-137,459,334

External References & Databases

Ensembl (ENSG00000165802)NCBI Gene (26012)OMIM (608137)HGNC:29843GenCCUniProt (Q6X4W1)AlphaFoldClinVar (NSMF)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~11.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadismSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018555

Submitter: Orphanet

hypogonadotropic hypogonadism 9 with or without anosmiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013911

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 9 with or without anosmiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013911

Submitter: Ambry Genetics

hypogonadotropic hypogonadism 9 with or without anosmiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013911

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 9 with or without anosmiaAD

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease

Comments: Syngergistic effects (eg, with FGFR1) have been reported

Refs: 15362570; 17235395; 21300340; 21700882; 22035731Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSMF variants in ClinVar

7 Conditions Cataloged
not providedTotal: 128
not specifiedTotal: 93
NSMF-related disorderTotal: 18
Hypogonadotropic hypogonadism 9 with or without anosmiaTotal: 12
EBV-positive nodal T- and NK-cell lymphomaTotal: 1
Male infertility with azoospermia or oligozoospermia due to single gene mutationTotal: 1
Pituitary stalk interruption syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001130969.3. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
40
clinvar
5
clinvar
 46
missense
108
clinvar
7
clinvar
1
clinvar
 116
nonsense
1
clinvar
2
clinvar
 3
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
5
clinvar
 6
Total11117476172

Highest pathogenic variant AF is 0.000028382447

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001130969.3RefSeqNP_001124441.116MANE Select
ENST00000371475.9EnsemblENSP00000360530.316MANE Select
NM_001130970.2RefSeqNP_001124442.115Standard
NM_001130971.2RefSeqNP_001124443.114Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • positive regulation of protein dephosphorylation
  • regulation of neuron apoptotic process
  • regulation of neuronal synaptic plasticity
  • regulation of dendrite morphogenesis
  • cellular response to amino acid stimulus

Molecular Function

  • calcium-dependent protein binding

Cellular Component

  • nucleus
  • nuclear envelope
  • nucleoplasm
  • nuclear euchromatin
  • cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371475
Coding exons
16
Length
11765
Individuals with no LoFs
125706
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125712
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.882333290.7080.00002283458
Missense (PolyPhen)80132.130.605471414
Synonymous-1.821571311.200.000009331025
Loss of Function3.86729.70.2360.00000160324

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000550.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000440.000044rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes. Part of the cAMP response element-binding protein (CREB) shut-off signaling pathway. Stimulates outgrowth of olfactory axons and migration of gonadotropin-releasing hormone (GnRH) and luteinizing-hormone-releasing hormone (LHRH) neuronal cells. {ECO:0000269|PubMed:20025934}.;
Disease
DISEASE: Hypogonadotropic hypogonadism 9 with or without anosmia (HH9) [MIM:614838]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:15362570, ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. The genetics of hypogonadotropic hypogonadism involves various modes of transmission. Oligogenic inheritance has been reported in some patients carrying mutations in NSMF as well as in other HH-associated genes including FGFR1 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.;

Recessive Scores

pRec
0.238

Intolerance Scores

RVIS EVS
-0.54
RVIS percentile EVS
20.26

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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