SEPTIN5

Chr 22

septin 5

Also known as: CDCREL, CDCREL-1, CDCREL1, H5, HCDCREL-1, PNUTL1, SEPT5, Septin-5

NCBI Gene: 5413 ENSG00000184702 UniProt: Q99719

SEPTIN5 encodes a filament-forming cytoskeletal GTPase that regulates cytoskeletal organization and may function in cytokinesis and platelet secretion. The gene is highly constrained against loss-of-function variants and is located in the 22q11 region that is frequently deleted in DiGeorge and velocardiofacial syndromes. Mutations in SEPTIN5 itself have not been established as a cause of Mendelian disease, though the gene's involvement in chromosomal rearrangements has been reported in acute myeloid leukemia.

ResearchSummary from RefSeq, UniProt

This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is mapped to 22q11, the region frequently deleted in DiGeorge and velocardiofacial syndromes. A translocation involving the MLL gene and this gene has also been reported in patients with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. The presence of a non-consensus polyA signal (AACAAT) in this gene also results in read-through transcription into the downstream neighboring gene (GP1BB; platelet glycoprotein Ib), whereby larger, non-coding transcripts are produced. [provided by RefSeq, Dec 2010]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.36

Clinical Summary— SEPTIN5

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.36LOEUF

pLI 0.927

Z-score 3.70

OE 0.14 (0.06–0.36)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.63Z-score

OE missense 0.53 (0.46–0.61)

128 obs / 243.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.06–0.36)

0≤0.351.4

Missense OE?0.53 (0.46–0.61)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 3 / 21.6Missense obs/exp: 128 / 243.5Syn Z: -0.75

This gene — mechanism propensity

0.6744th %ile

GOF

0.6541th %ile

LOF

0.4233th %ile

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

DNprediction above median

GOFprediction above median

LOFLOEUF 0.36

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.