Hypogonadotropic hypogonadism 9 with or without anosmia

disease

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Also known as HH9hypogonadotropic hypogonadism caused by mutation in NSMFNSMF hypogonadotropic hypogonadism

Summary

Hypogonadotropic hypogonadism 9 with or without anosmia (MONDO:0013911) is a disease caused by NSMF (GenCC Strong), with 1 cohort gene.

At a glance

Causal gene: NSMF (GenCC Strong)
Cohort genes: 1
ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 9 with or without anosmia
Mondo ID	MONDO:0013911
OMIM	614838
DOID	DOID:0090085
UMLS	C3553842
MedGen	766756
GARD	0015850
Is cancer (heuristic)	no

Also known as: HH9 · hypogonadotropic hypogonadism 9 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in NSMF · NSMF hypogonadotropic hypogonadism

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kallmann syndrome › hypogonadotropic hypogonadism 9 with or without anosmia

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

12 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 2 risk factor, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2524	NM_001130969.3(NSMF):c.1438A>G (p.Thr480Ala)	LOC126860797	risk factor	no assertion criteria provided
2525	NM_001130969.3(NSMF):c.1132-23_1132-15del	NSMF	risk factor	no assertion criteria provided
638190	NM_001130969.3(NSMF):c.1261C>T (p.Leu421Phe)	LOC126860797	Uncertain significance	no assertion criteria provided
976066	NM_001130969.3(NSMF):c.1435A>G (p.Arg479Gly)	LOC126860797	Uncertain significance	criteria provided, single submitter
2434447	NM_001130969.3(NSMF):c.194C>A (p.Pro65His)	NSMF	Uncertain significance	criteria provided, single submitter
3235192	NM_001130969.3(NSMF):c.919G>C (p.Asp307His)	NSMF	Uncertain significance	criteria provided, single submitter
3596944	NM_001130969.3(NSMF):c.383G>A (p.Arg128Gln)	NSMF	Uncertain significance	criteria provided, single submitter
3891862	NM_001130969.3(NSMF):c.586C>G (p.Arg196Gly)	NSMF	Uncertain significance	criteria provided, single submitter
426277	NM_001130969.3(NSMF):c.241G>A (p.Gly81Ser)	NSMF	Uncertain significance	criteria provided, multiple submitters, no conflicts
931977	NM_001130969.3(NSMF):c.586C>T (p.Arg196Cys)	NSMF	Uncertain significance	criteria provided, single submitter
1599715	NM_001130969.3(NSMF):c.1132-22_1132-15del	NSMF	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3780044	NM_001130969.3(NSMF):c.779+182A>G	NSMF	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
NSMF	Strong	Autosomal dominant	hypogonadotropic hypogonadism 9 with or without anosmia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NSMF	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism

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
NSMF	HGNC:29843	ENSG00000165802	Q6X4W1	NMDA receptor synaptonuclear signaling and neuronal migration factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NSMF	NMDA receptor synaptonuclear signaling and neuronal migration factor	Couples NMDA-sensitive glutamate receptor signaling to the nucleus and triggers long-lasting changes in the cytoarchitecture of dendrites and spine synapse processes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NSMF	Other/Unknown	no		NSMF, IQ_SCN5A_C

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
anterior cingulate cortex	1
cingulate cortex	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NSMF	251	ubiquitous	marker	cortical plate, anterior cingulate cortex, cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSMF	615

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NSMF	Q6X4W1	65.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
cellular response to gonadotropin stimulus	1	2808.7×	0.002	NSMF
cellular response to electrical stimulus	1	1296.3×	0.002	NSMF
positive regulation of neuron migration	1	991.3×	0.002	NSMF
regulation of dendrite morphogenesis	1	732.7×	0.002	NSMF
regulation of neuron apoptotic process	1	702.2×	0.002	NSMF
regulation of neuronal synaptic plasticity	1	674.1×	0.002	NSMF
cellular response to amino acid stimulus	1	306.4×	0.003	NSMF

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
NSMF	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NSMF

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)
NSMF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: NSMF