rs603424 (chr10:100315722-G-A)
Summary¶
rs603424 is a single nucleotide polymorphism (G>A transition at chr10:100315722 in GRCh38) that sits in an enhancer element governing fatty acid metabolism. The variant is strongly associated with changes in the ratio of 16:1 to 18:0 lipid species. While standard variant-to-gene (V2G) mapping tools often prioritize the proximal gene PKD2L1, multiple lines of computational and empirical evidence confirm this element acts as a regulatory enhancer for SCD specifically in adipose tissue.
Functional Evidence¶
This locus presents a classic example of an enhancer with significant blind spots in standard automated annotation pipelines, requiring orthogonal validation to interpret correctly.
1. In-Silico Mutagenesis (AlphaGenome)¶
Deep-learning variant effect prediction using AlphaGenome strongly predicts that the G>A mutation destroys a regulatory element. AlphaGenome's sequence-based model predicts a massive loss of chromatin accessibility (DNASE) across multiple tissues, with top raw score reductions in stromal cells, fibroblasts, and importantly, adipocytes.
Furthermore, AlphaGenome predicts highly significant downstream RNA downregulation (quantile scores > 0.99) for both SCD and PKD2L1 exclusively in adipose tissues (subcutaneous adipose tissue, omental fat pad, and mesenteric fat pad).
2. Empirical eQTLs (GTEx)¶
Data from GTEx confirms the predictions of the sequence models. rs603424 acts as a highly significant eQTL for SCD specifically in: - Adipose - Visceral (Omentum) - Adipose - Subcutaneous - Breast - Mammary Tissue
It is also an eQTL for PKD2L1 in subcutaneous adipose tissue and brain. Because it regulates both genes in adipose tissue, proximity-based mapping tools and algorithms like Open Targets (which rely heavily on standard eQTL pipelines) often misassign the target solely to PKD2L1, missing the causal metabolic biology linking SCD to the observed lipid phenotypes.
3. Evolutionary Conservation¶
The base at chr10:100315722 exhibits a phyloP100way score of -0.48, meaning it is not evolutionarily conserved across vertebrates. Like many metabolic and lipid-regulating enhancers, it appears to be fast-evolving or primate-specific, which explains why it is not annotated as a classic high-confidence element in databases relying on deep conservation (e.g., standard ENCODE Type A elements).