KHDC3L

Chr 6AR

KH domain containing 3 like, subcortical maternal complex member

NCBI Gene: 154288 ENSG00000203908 UniProt: Q587J8

Component of the subcortical maternal complex (SCMC), a multiprotein complex that plays a key role in early embryonic development (By similarity). The SCMC complex is a structural constituent of cytoplasmic lattices, which consist in fibrous structures found in the cytoplasm of oocytes and preimplantation embryos (By similarity). They are required to store maternal proteins critical for embryonic development, such as proteins that control epigenetic reprogramming of the preimplantation embryo, and prevent their degradation or activation (By similarity). KHDC3 ensures proper spindle assembly by regulating the localization of AURKA via RHOA signaling and of PLK1 via a RHOA-independent process (By similarity). Required for the localization of MAD2L1 to kinetochores to enable spindle assembly checkpoint function (By similarity). As part of the OOEP-KHDC3 scaffold, recruits BLM and TRIM25 to DNA replication forks, thereby promoting the ubiquitination of BLM by TRIM25, enhancing BLM retainment at replication forks and therefore promoting stalled replication fork restart (By similarity). Regulates homologous recombination-mediated DNA repair via recruitment of RAD51 to sites of DNA double-strand breaks, and sustainment of PARP1 activity, which in turn modulates downstream ATM or ATR activation (PubMed:31609975). Activation of ATM or ATR in response to DNA double-strand breaks may be cell-type specific (By similarity). Its role in DNA double-strand break repair is independent of its role in restarting stalled replication forks (By similarity). Promotes neural stem cell neurogenesis and neuronal differentiation in the hippocampus (By similarity). May regulate normal development of learning, memory and anxiety (By similarity). Capable of binding RNA (By similarity)

Primary Disease Associations & Inheritance

Hydatidiform mole, recurrent, 2MIM #614293

ClinVar variants

Pathogenic / LP

0.12

pLI score

Active trials

Clinical Summary— KHDC3L

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Population Constraint (gnomAD)

Low constraint (pLI 0.12) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 Pathogenic / Likely Pathogenic· 39 VUS of 62 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.16LOEUF

pLI 0.123

Z-score 1.36

OE 0.37 (0.15–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.20Z-score

OE missense 0.95 (0.83–1.10)

139 obs / 145.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.15–1.16)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.83–1.10)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.83

0≤1.21.6

LoF obs/exp: 2 / 5.4Missense obs/exp: 139 / 145.7Syn Z: 1.06