Quick Start

This tutorial provides a comprehensive example of how to use the HGVS package. Specifically, we’ll:

  • install hgvs
  • parse a genomic variant
  • project the genomic variant to all transcripts
  • infer the amino acid changes for coding transcripts

We’ll use rs397509113 in BRCA1. This variant is coincident with an exon in 3 coding transcripts, an intron in 2 other coding transcripts, and a non-coding transcript.

transcript (c.) protein (p.) comment
NM_007294.3:c.3844del NP_009225.1:p.(Glu1282AsnfsTer25)  
NM_007297.3:c.3703del NP_009228.2:p.(Glu1235AsnfsTer25)  
NM_007300.3:c.3844del NP_009231.2:p.(Glu1282AsnfsTer25)  
NM_007298.3:c.788-655del NP_009229.2:p.? intronic variant
NM_007299.3:c.788-655del NP_009230.2:p.? intronic variant
NR_027676.1:n.3980del non-coding non-coding transcript

Install hgvs

For this demo, you’ll obviously need hgvs. In a reasonably modern environment, the following should suffice:

$ pip install hgvs

More detailed installation instructions are in Installing hgvs.

Start hgvs-shell

The hgvs package includes an executable called hgvs-shell, which sets up hgvs for you. On the command line, type:

$ hgvs-shell

This is approximately the same thing as:

$ IPython
>>> from hgvs.easy import *

hgvs.easy connects to data sources and initializes commonly used objects that provide most functionality.

Note

Variant validation, normalization, and projection require access to external data, specifically exon structures, transcript alignments, and protein accessions. Right now, the only source of this data is via the UTA sister projects. When you import hgvs.easy, you will connect to publicly available data sources. If you want more information on the architecture of hgvs and UTA, see Introduction. See Installing hgvs for information about installing data sources locally for speed and privacy.

Parse the genomic variant

In the hgvs-shell, do:

>>> var_g = parse("NC_000017.11:g.43091687delC")

Note

All functionality in hgvs is provided by Python classes. hgvs.easy exposes common methods with functional forms also, which are used in this quick start guide. For example, parse(...) above actually calls `parser.parse(...), where parser is an instance of the hgvs.parser.Parser class.

Parsing a variant results in objects that represent the variant. A SequenceVariant object is comprised of an accession (ac), an HGVS sequence type (c,g,m,n,r,p), and 0 or more specific sequence changes (posedit – a POSition and EDIt).:

>>> var_g
SequenceVariant(ac=NC_000017.11, type=g, posedit=43091687del)

The posedit is itself an object of the hgvs.posedit.PosEdit class:

>>> var_g.posedit
PosEdit(pos=43091687, edit=del, uncertain=False)

The pos (position) and edit attributes are also objects that can represent intervals and more complex edit operations like indels. The uncertain flag enables representation of HGVS uncertainty (typically with parentheses around the uncertain component). “stringifying” a variant regenerates an HGVS variant:

>>> str(var_g)
'NC_000017.11:g.43091687del'

>>> "This is a variant: {v}".format(v=var_g)
'This is a variant: NC_000017.11:g.43091687del'

And, in Python 3, stringification works in f-strings, like so:

> >> f"{var_g}"
'NC_000017.11:g.43091687del'

Validating and Normalizing Variants

hgvs provides functionality to validate and normalize variants:

>>> normalize(var_g)
SequenceVariant(ac=NC_000017.11, type=g, posedit=43091688del)

>>> validate(var_g)
True

Projecting variants between sequences

When two sequences have alignments available in , a variant may be “projected” from one sequence to the other. hgvs supports projecting variants

  • from g to c, n
  • from c to g, n, p
  • from n to c, g

The hgvs.assemblymapper.AssemblyMapper class provides a high-level interface to variant projection. hgvs.easy initializes AssemblyMapper instances for GRCh37 and GRCh37 as am37 and am38 respectively. For example:

>>> transcripts = am38.relevant_transcripts(var_g)
>>> sorted(transcripts)
['NM_007294.3', 'NM_007297.3', 'NM_007298.3', 'NM_007299.3', 'NM_007300.3', 'NR_027676.1']

We can now project the genomic variant, var_g, to each of these transcripts using the g_to_t function, and the transcript variant to a protein sequnce using the t_to_p function.

>>> for ac in get_relevant_transcripts(var_g):
...     var_t = g_to_t(var_g, ac)
...     var_p = t_to_p(var_t)
...     print("-> " + str(var_t) + " (" + str(var_p) + ") ")
...
-> NM_007294.3:c.3844del (NP_009225.1:p.(Glu1282AsnfsTer25))
-> NM_007297.3:c.3703del (NP_009228.2:p.(Glu1235AsnfsTer25))
-> NM_007298.3:c.788-655del (NP_009229.2:p.?)
-> NM_007299.3:c.788-655del (NP_009230.2:p.?)
-> NM_007300.3:c.3844del (NP_009231.2:p.(Glu1282AsnfsTer25))
-> NR_027676.1:n.3980del (non-coding)

In hgvs, the t type can be either c or n. Only variants on coding sequences (c.) can be projected to a protein sequence. As a special case, t_to_p returns “non-coding” when the input variant is on a non-coding sequence.