Presentation on the LRG project by Joanella Morales at GRC/GIAB workshop at ASHG 2018 meeting

1. How does it relate to MANE and GRC?
The Locus Reference Genomic (LRG) project
Joannella Morales, PhD
Project Manager
EMBL-EBI
jmorales@ebi.ac.uk

2. • Joint effort between the NCBI and EMBL-EBI since 2008
• Recurrent requests from clinical community for tools to ensure efficient and
consistent variant reporting
• Challenges:
• Keeping track of clinically-relevant variants over time
• Changes to genome assembly
• Changes to genes and transcripts
• Inconsistent reporting of variants due to lack of approved/standardized sequences
• Multiple genomic haplotypes
• Multiple transcript sets
• Multiple versioned sequences
The LRG Project
For example, PAX6 (eye)
11 NMs
81 ENSTs
Which sequence to use??

3. LRG records
• Manually curated
• Contain stable reference sequences (do not version)
• Sequences selected by curators in collaboration with locus-specific
experts
• Used for reporting of clinically-relevant variants – HGVS compatible
• Genomic - LRG_1:g.15178G>A
• Transcript - LRG_1t1:c.2156G>A
• Protein - LRG_1p1:p.Gly719Asp

4. LRG Records

5. LRG and MANE convergence
• LRG Project not scalable since it is 100% manual and there are thousands of clinical genes
• Automation useful, but manual oversight required to ensure meaningful in the clinical
context
• Evolution of LRG -> MANE Plus?
• Same methodology as MANE project
• Extended to cover transcripts that are well-supported, tissue-specific or relevant to specific user
groups; a cut of the highest value representing most exons with well-expressed splice forms
• LRG Team
• Manual effort to review transcripts for MANE Plus? set
• Engage with locus-specific experts
• Continue to support existing LRG records

6. LRG and GRC
• LRGs are independent of GRCh38
• Many LRG users require or prefer alternate sequences
• Issues in GRCh38 (e.g. ABO)
• GRCh38 represents a minor allele (e.g. HTT, EIF2AK3)
• Vast majority of LRGs match GRCh38, but several LRGs contain non-GRCh38
sequences

7. Annotation about mismatches
When the GRCh38 allele is not the preferred allele

8. LRG and GRC
• This user group cannot be served by MANE project (due to GRCh38
dependency)
• LRG project will continue to create records for genes where an alternate
genomic sequence is required
• LRG project will continue to work with GRC to create Novel patches, when
possible

9. Questions?