SEMA5B

Chr 3

semaphorin 5B

Also known as: SEMAG, SemG

NCBI Gene: 54437 ENSG00000082684 UniProt: Q9P283 OMIM: 609298

The protein is a secreted semaphorin that regulates axon growth during nervous system development and may act as a positive axonal guidance cue through its Sema domain and thrombospondin repeats. Mutations cause autosomal recessive developmental delay with autism spectrum disorder and seizures, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants (LOEUF 0.604), reflecting its critical role in neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the semaphorin protein family which regulates axon growth during development of the nervous system. The encoded protein has a characteristic Sema domain near the N-terminus, through which semaphorins bind to plexin, and five thrombospondin type 1 repeats in the C-terminal region of the protein. The protein product may be cleaved and exist as a secreted molecule (PMID: 19463192). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— SEMA5B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

176 VUS of 209 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 4.09

OE 0.44 (0.32–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.50Z-score

OE missense 0.84 (0.79–0.90)

625 obs / 740.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.32–0.60)

0≤0.351.4

Missense OE?0.84 (0.79–0.90)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 27 / 61.6Missense obs/exp: 625 / 740.1Syn Z: 0.03

This gene — mechanism propensity

0.6745th %ile

GOF

0.7029th %ile

LOF

0.3454th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

209 submitted variants in ClinVar

ClinVar

Classification Summary

VUS176

Likely Benign4

Benign3

176

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	176	0	0	176
Likely Benign	4	0	0	4
Benign	1	1	1	3
Total	181	1	1	183

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap SEMA5B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →