KNL1

Chr 15

kinetochore scaffold 1

Also known as: AF15Q14, CASC5, CT29, D40, MCPH4, PPP1R55, Spc7, hKNL-1

NCBI Gene: 57082 ENSG00000137812 UniProt: Q8NG31

The protein functions as a scaffold component of the outer kinetochore complex that mediates chromosome-microtubule attachments during cell division and recruits spindle assembly checkpoint proteins to ensure proper chromosome segregation. Mutations cause autosomal recessive primary microcephaly-4, a disorder characterized by severely reduced brain size present from birth. The gene shows high constraint against loss-of-function variants (LOEUF 0.314), indicating that complete loss of protein function is poorly tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMicrocephaly 4, primary, autosomal recessive

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· G2P

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?

0.31LOEUF

pLI 0.783

Z-score 6.86

OE 0.21 (0.15–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.01Z-score

OE missense 1.00 (0.95–1.05)

1166 obs / 1165.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.21 (0.15–0.31)

0≤0.351.4

Missense OE?1.00 (0.95–1.05)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 19 / 88.8Missense obs/exp: 1166 / 1165.2Syn Z: 0.44

Background carrier burden — how many people carry a rare variant somewhere in KNL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 23

3,041 rare PASS variants

Rare truncating (LoF)

1 in 880

173 rare PASS variants

Rare synonymous (reference)

1 in 59

959 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KNL1. 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 32	1 in 990
South Asian	~43k	1 in 20	1 in 2,200
Remaining (unassigned)	~30k	1 in 16	1 in 1,000
European (Finnish)	~27k	1 in 60	1 in 4,400
Admixed American	~22k	1 in 21	1 in 1,200
African / African American	~21k	1 in 19	1 in 840
East Asian	~20k	1 in 19	1 in 2,200
Ashkenazi Jewish	~13k	1 in 120	1 in 680
Middle Eastern	~2,884	1 in 21	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 25 coding exons well covered in gnomAD exomes; exons 7, 8 poorly covered; exons 2, 3, 4, 5, 6 and 9 more marginal. Genomes: all 25.? see exons ↓