trinucleotide expansion up to 19.02 --> inframe deletion in 19.04

deniseOme commented 5 years ago

Genetic evidence linking HTT to huntington disease has changed from trinucleotide expansion to inframe deletion.

From Entrez Gene: "Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological"

This data comes from ClinVar via EVA. Has anything changed in the JSON from EVA between 19.02 and 19.04 for HTT and Huntington?

Some notes:

some past conversations: https://github.com/The-Sequence-Ontology/SO-Ontologies/issues/399#issuecomment-302463868
I'd have thought that inframe deletion is actually wrong, it could be inframe insertion but not deletion
we list the variant as rs71180116 (rather than RCV000032098) in the second (mutation) column in the genetic associations page. Using the rs ID instead of RCV ID, we now point to Ensembl (instead of pointing to ClinVar ), which calls this "inframe deletion". Is that why we've changed from trinucleotide expansion to inframe deletion? Can we override the VEP results? VEP consequence term for rs193922926 is overridden for this example:

https://www.targetvalidation.org/evidence/ENSG00000124788/Orphanet_98755?view=sec:genetic_association

(trinucleotide repeat expansion in the Platform, coding sequence variant in Ensembl)

many other repeat expansion disorders in the Platform have their variants still "trinucleotide repeat expansion" e.g. FMR1 in Fragile X syndrome, ATXN7 in Spinocerebellar ataxia type 7, ATXN1 in Spinocerebellar ataxia type 1, DMPK in Steinert myotonic dystrophy

afaulconbridge commented 5 years ago

Is this relevant: https://github.com/opentargets/data_release/wiki/OT007-SNP2GENE-Pipeline#adding-trinucleotide-disease-annotation-eva-only ?

AsierGonzalez commented 5 years ago

This does not look like an "issue" to me, just a data update. EVA evidence data has changed substantially for the 19.04 release because ClinVar added many new rsIds in January. In this particular case, although RCV000032098 is still associated with HTT in Huntington's disease, it seems that priority is given to the rsID, which is new:

19.02_cttv012-29-01-2019.json

{
  "alleleOrigin": "germline",
  "phenotype": "http://www.orpha.net/ORDO/Orphanet_399",
  "gene": "ENSG00000197386",
  "clinvarAccession": "RCV000032098",
  "variant_id": "RCV000032098"
}

19.04_cttv012-10-04-2019.json

{
  "alleleOrigin": "germline",  
  "phenotype": "http://www.orpha.net/ORDO/Orphanet_399",
  "gene": "ENSG00000197386",
  "clinvarAccession": "RCV000032098",
  "variant_id": "rs71180116"
}

This is probably something we should discuss with EVA.

iandunham commented 5 years ago

I think itis an issue, in that VEP does not accurately call the consequence of rs71180116 because the polarity of the alleles is wrong. The disease associated allele is the trinucleotide expansion allele (erroneously represented as an insertion) rather than the smaller "deletion" allele. The 'normal' is the deleted/non-expanded allele. I think this is why we have the over-ride file that adam points to above which corrects these consequences for certain mutations. As a temporary fix we should include rs71180116 in that file, and also talk to EVA about how mutations are represnted in Clinvar - we may not be able to do anything about that

AsierGonzalez commented 5 years ago

Out of the 23 trinucleotide expansions in the ot_trinucleotide.txt file, only 12 appear in the 19.04 EVA evidence file and three of them have the wrong functional consequence annotated (see rows in bold):

ClinVar Accession	Variant id	Gene id	Phenotype	Functional Consequence
RCV000011272	rs193922937	ENSG00000155966	FRAXE intellectual disability	trinucleotide_repeat_expansion
RCV000003729	rs193922928	ENSG00000066427	Spinocerebellar ataxia type 3	trinucleotide_repeat_expansion
RCV000004184	RCV000004184	ENSG00000165060	Friedreich ataxia	trinucleotide_repeat_expansion
RCV000009015	RCV000009015	ENSG00000141837	Spinocerebellar ataxia type 6	trinucleotide_repeat_expansion
RCV000019124	RCV000019124	ENSG00000169714	Proximal myotonic myopathy	trinucleotide_repeat_expansion
RCV000191939	rs1555397179	ENSG00000066427	Spinocerebellar ataxia type 3	trinucleotide_repeat_expansion
RCV000483474	rs3032358	ENSG00000169083	Kennedy disease	inframe_deletion
RCV000005352	RCV000005352	ENSG00000104936	Steinert myotonic dystrophy	trinucleotide_repeat_expansion
RCV000008537	rs193922926	ENSG00000124788	Spinocerebellar ataxia type 1	trinucleotide_repeat_expansion
RCV000032098	rs71180116	ENSG00000197386	Huntington disease	inframe_deletion
RCV000032099	rs71180116	ENSG00000197386	Huntington disease	inframe_deletion
RCV000162201	rs193922936	ENSG00000102081	Fragile X syndrome	trinucleotide_repeat_expansion

I'm in touch with Kirill in EVA team to get this sorted for the next release.

AsierGonzalez commented 5 years ago

After talking to EVA, it has been found that the issue is caused by the approach used to pair ClinVar records with the mapping provided:

Try pairing using rsID
Or, if not present in the mappings file, use nsvID
Or, if not present, use full variant description (e. g. 10:100749815-100749815:1/A)
Finally, if none of the above worked, use ClinVar RCV ID

RCV000032098 and RCV000032099 are masked by rs71180116 and the following entry in the mapping file:

rs71180116  1   ENSG00000197386 HTT inframe_deletion    0

Similarly, the entry masking RCV000483474 is this:

X:67545318-67545320:1/-    1    ENSG00000169083    AR    inframe_deletion    0

Those two rows have been manually removed from the mapping file returned to EVA and now the functional consequence of those variants is trinucleotide_repeat_expansion as expected. However, they still have an associated rsID, so the link may still point to an Ensembl website with the wrong function annotation. This will be furter discussed with EVA.