Hypogonadotropic hypogonadism 16 with or without anosmia

Summary

Hypogonadotropic hypogonadism 16 with or without anosmia (MONDO:0013961) is a disease caused by SEMA3A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SEMA3A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypogonadotropic hypogonadism 16 with or without anosmia
Mondo ID	MONDO:0013961
OMIM	614897
DOID	DOID:0090080
UMLS	C3554021
MedGen	766935
GARD	0015878
Is cancer (heuristic)	no

Also known as: HH16 · hypogonadotropic hypogonadism 16 with or without anosmia · hypogonadotropic hypogonadism caused by mutation in SEMA3A · SEMA3A hypogonadotropic hypogonadism

Data availability: 20 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 16 with or without anosmia

Related subtypes (17): hypogonadotropic hypogonadism 2 with or without anosmia, hypogonadotropic hypogonadism 3 with or without anosmia, hypogonadotropic hypogonadism 1 with or without anosmia, hypogonadotropic hypogonadism 4 with or without anosmia, hypogonadotropic hypogonadism 5 with or without anosmia, hypogonadotropic hypogonadism 6 with or without anosmia, hypogonadotropic hypogonadism 8 with or without anosmia, hypogonadotropic hypogonadism 9 with or without anosmia, hypogonadotropic hypogonadism 11 with or without anosmia, hypogonadotropic hypogonadism 14 with or without anosmia, hypogonadotropic hypogonadism 15 with or without anosmia, hypogonadotropic hypogonadism 17 with or without anosmia, hypogonadotropic hypogonadism 18 with or without anosmia, hypogonadotropic hypogonadism 19 with or without anosmia, hypogonadotropic hypogonadism 20 with or without anosmia, hypogonadotropic hypogonadism 21 with or without anosmia, hypogonadotropic hypogonadism 22 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

20 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 risk factor, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
625633	GRCh37/hg19 7q21.11(chr7:83664877-83740076)	SEMA3A	Pathogenic	criteria provided, single submitter
3255611	NM_006080.3(SEMA3A):c.333+2T>C	SEMA3A	Likely pathogenic	criteria provided, single submitter
39715	NC_000007.14:g.(83833300_?)_(?_84046323)del	LOC129998733	risk factor	no assertion criteria provided
1325878	NM_006080.3(SEMA3A):c.590G>A (p.Arg197Gln)	SEMA3A	risk factor	no assertion criteria provided
1325880	NM_006080.3(SEMA3A):c.1850G>A (p.Arg617Gln)	SEMA3A	risk factor	no assertion criteria provided
39717	NM_006080.3(SEMA3A):c.1613_1626del (p.Asp538fs)	SEMA3A	risk factor	no assertion criteria provided
2636001	NM_006080.3(SEMA3A):c.1450C>T (p.Arg484Trp)	SEMA3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68831	NM_006080.3(SEMA3A):c.1198A>G (p.Ile400Val)	SEMA3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68836	NM_006080.3(SEMA3A):c.458A>G (p.Asn153Ser)	SEMA3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325879	NM_006080.3(SEMA3A):c.1372G>A (p.Val458Ile)	SEMA3A	Uncertain significance	criteria provided, single submitter
3355735	NM_006080.3(SEMA3A):c.869G>A (p.Arg290His)	SEMA3A	Uncertain significance	criteria provided, single submitter
3356381	NM_006080.3(SEMA3A):c.270+6A>C	SEMA3A	Uncertain significance	criteria provided, single submitter
3381953	NM_006080.3(SEMA3A):c.607C>T (p.Arg203Ter)	SEMA3A	Uncertain significance	criteria provided, single submitter
3393122	NM_006080.3(SEMA3A):c.1873G>A (p.Asp625Asn)	SEMA3A	Uncertain significance	criteria provided, single submitter
3892381	NM_006080.3(SEMA3A):c.1753A>G (p.Ile585Val)	SEMA3A	Uncertain significance	criteria provided, single submitter
68833	NM_006080.3(SEMA3A):c.2062A>G (p.Thr688Ala)	SEMA3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
68835	NM_006080.3(SEMA3A):c.2198G>A (p.Arg733His)	SEMA3A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1632292	NM_006080.3(SEMA3A):c.1302_1303inv (p.Val435Ile)	SEMA3A	Likely benign	criteria provided, multiple submitters, no conflicts
39716	NM_006080.3(SEMA3A):c.1303G>A (p.Val435Ile)	SEMA3A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
768175	NM_006080.3(SEMA3A):c.1000A>G (p.Ile334Val)	SEMA3A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
SEMA3A	Strong	Autosomal dominant	hypogonadotropic hypogonadism 16 with or without anosmia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome

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
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom

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
colonic epithelium	1
cortical plate	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEMA3A	2,069

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEMA3A	Q14563	84.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion	1	761.3×	0.004	SEMA3A
Sema3A PAK dependent Axon repulsion	1	671.8×	0.004	SEMA3A
CRMPs in Sema3A signaling	1	634.4×	0.004	SEMA3A
Semaphorin interactions	1	393.8×	0.004	SEMA3A
Axon guidance	1	45.1×	0.027	SEMA3A
Nervous system development	1	42.9×	0.027	SEMA3A
Developmental Biology	1	14.5×	0.069	SEMA3A

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
regulation of axon extension involved in axon guidance	1	8426.0×	0.001	SEMA3A
sensory system development	1	5617.3×	0.001	SEMA3A
basal dendrite arborization	1	5617.3×	0.001	SEMA3A
sympathetic neuron projection guidance	1	4213.0×	0.001	SEMA3A
trigeminal nerve structural organization	1	2808.7×	0.001	SEMA3A
sympathetic neuron projection extension	1	2808.7×	0.001	SEMA3A
branchiomotor neuron axon guidance	1	2106.5×	0.001	SEMA3A
facial nerve structural organization	1	1872.4×	0.001	SEMA3A
sympathetic ganglion development	1	1872.4×	0.001	SEMA3A
neural crest cell migration involved in autonomic nervous system development	1	1872.4×	0.001	SEMA3A
axonogenesis involved in innervation	1	1685.2×	0.001	SEMA3A
axon extension involved in axon guidance	1	1532.0×	0.001	SEMA3A
nerve development	1	936.2×	0.002	SEMA3A
sympathetic nervous system development	1	936.2×	0.002	SEMA3A
olfactory bulb development	1	766.0×	0.002	SEMA3A
motor neuron axon guidance	1	702.2×	0.002	SEMA3A
negative chemotaxis	1	648.1×	0.002	SEMA3A
semaphorin-plexin signaling pathway	1	401.2×	0.003	SEMA3A
neural crest cell migration	1	337.0×	0.004	SEMA3A
negative regulation of neuron projection development	1	237.3×	0.005	SEMA3A
positive regulation of JNK cascade	1	163.6×	0.007	SEMA3A
neuron migration	1	133.8×	0.008	SEMA3A
axon guidance	1	90.6×	0.012	SEMA3A
positive regulation of cell migration	1	61.7×	0.016	SEMA3A

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
SEMA3A	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	1	SEMA3A
E	Difficult family or no structure, no drug	0

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)
SEMA3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.