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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.60

LOEUF

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in SEMA5B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 41

1,696 rare PASS variants

Rare truncating (LoF)

1 in 520

188 rare PASS variants

Rare synonymous (reference)

1 in 70

767 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SEMA5B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 60	1 in 560
South Asian	~43k	1 in 34	1 in 1,100
Remaining (unassigned)	~30k	1 in 32	1 in 350
European (Finnish)	~27k	1 in 110	1 in 3,100
Admixed American	~22k	1 in 38	1 in 580
African / African American	~21k	1 in 31	1 in 750
East Asian	~20k	1 in 48	1 in 1,000
Ashkenazi Jewish	~13k	1 in 130	1 in 970
Middle Eastern	~2,884	1 in 38	1 in 570

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 22 coding exons well covered in gnomAD exomes; exon 8 marginal. Genomes: all 22.? see exons ↓