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Merge pull request #727 from broadinstitute/jg/fix_pext_csq_filter
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Fix `tx_filter_variants_by_csqs` to correctly handle the `ignore_splicing` parameter
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@jkgoodrich
jkgoodrich authored Aug 23, 2024
2 parents ed32ff1 + c88ab80 commit 31a2819
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Showing 4 changed files with 216 additions and 12 deletions.
1 change: 1 addition & 0 deletions .github/workflows/ci.yml
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Expand Up @@ -27,6 +27,7 @@ jobs:
pip install wheel
pip install -r requirements.txt
pip install -r requirements-dev.txt
curl -sSL https://broad.io/install-gcs-connector | python3 - --auth-type UNAUTHENTICATED
- name: Check formatting
run: black --check gnomad tests
- name: Check imports
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34 changes: 22 additions & 12 deletions gnomad/utils/transcript_annotation.py
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Expand Up @@ -323,28 +323,38 @@ def tx_filter_variants_by_csqs(
lambda csq: hl.is_defined(csq.amino_acids) & (csq.amino_acids != "*")
]

keep_csqs = True
if ignore_splicing:
if filter_to_csqs is not None:
filter_to_csqs = [csq for csq in filter_to_csqs if csq not in CSQ_SPLICE]
else:
filter_to_csqs = CSQ_SPLICE
keep_csqs = False

if filter_to_csqs is not None:
logger.info("Adding most severe consequence to VEP transcript consequences...")
ht = process_consequences(
ht, vep_root=vep_root, has_polyphen=include_polyphen_prioritization
logger.info("Filtering VEP consequences to exclude splice consequences...")
ht = ht.annotate(
**{
vep_root: ht[vep_root].annotate(
transcript_consequences=ht[vep_root]
.transcript_consequences.map(
lambda csq: csq.annotate(
consequence_terms=csq.consequence_terms.filter(
lambda x: ~hl.literal(CSQ_SPLICE).contains(x)
)
)
)
.filter(lambda csq: hl.len(csq.consequence_terms) > 0)
)
}
)

logger.info("Processing VEP consequences...")
ht = process_consequences(
ht,
vep_root=vep_root,
has_polyphen=include_polyphen_prioritization,
)

return filter_vep_transcript_csqs(
ht,
vep_root=vep_root,
synonymous=False,
canonical=False,
protein_coding=filter_to_protein_coding,
csqs=filter_to_csqs,
keep_csqs=keep_csqs,
genes=filter_to_genes,
match_by_gene_symbol=match_by_gene_symbol,
additional_filtering_criteria=additional_filtering_criteria,
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7 changes: 7 additions & 0 deletions tests/resources/test_resource_utils.py
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Expand Up @@ -14,6 +14,13 @@
)


@pytest.fixture(autouse=True)
def reset_gnomad_public_resource_configuration():
"""Reset gnomAD public resource configuration after each test."""
yield
gnomad_public_resource_configuration.source = None


class TestTableResource:
"""Tests for TableResource."""

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186 changes: 186 additions & 0 deletions tests/utils/test_transcript_annotation.py
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Expand Up @@ -6,6 +6,7 @@
from gnomad.utils.transcript_annotation import (
clean_tissue_name_for_browser,
create_tx_annotation_by_region,
tx_filter_variants_by_csqs,
)


Expand Down Expand Up @@ -192,3 +193,188 @@ def test_create_tx_annotation_by_region(self, sample_hail_table: hl.Table) -> No

# Verify the result
assert result == expected_result


@pytest.fixture
def mock_vep_annotated_ht():
"""Create a mock Hail Table with VEP annotations."""
return hl.Table.parallelize(
[
{
"locus": hl.Locus("1", 861393, reference_genome="GRCh37"),
"alleles": ["G", "A"],
"vep": {
"transcript_consequences": [
{
"gene_id": "ENSG00000187634",
"gene_symbol": "SAMD11",
"transcript_id": "ENST00000342066",
"consequence_terms": [
"splice_region_variant",
"synonymous_variant",
],
"amino_acids": "V",
"biotype": "protein_coding",
"lof": None,
"lof_flags": None,
"canonical": 0,
},
{
"gene_id": "ENSG00000268179",
"gene_symbol": "AL645608.1",
"transcript_id": "ENST00000598827",
"consequence_terms": ["synonymous_variant"],
"amino_acids": "T",
"biotype": "protein_coding",
"lof": None,
"lof_flags": None,
"canonical": 1,
},
],
},
},
{
"locus": hl.Locus("1", 871274, reference_genome="GRCh37"),
"alleles": ["C", "A"],
"vep": {
"transcript_consequences": [
{
"gene_id": "ENSG00000187634",
"gene_symbol": "SAMD11",
"transcript_id": "ENST00000420190",
"consequence_terms": ["splice_region_variant"],
"amino_acids": None,
"biotype": "protein_coding",
"lof": None,
"lof_flags": None,
"canonical": 0,
}
]
},
},
{
"locus": hl.Locus("1", 871275, reference_genome="GRCh37"),
"alleles": ["C", "A"],
"vep": {
"transcript_consequences": [
{
"gene_id": "ENSG00000187634",
"gene_symbol": "SAMD11",
"transcript_id": "ENST00000420190",
"consequence_terms": [
"splice_region_variant",
"synonymous_variant",
],
"amino_acids": "A",
"biotype": "protein_coding",
"lof": None,
"lof_flags": None,
"canonical": 1,
}
]
},
},
{
"locus": hl.Locus("1", 1000, reference_genome="GRCh37"),
"alleles": ["T", "G"],
"vep": {
"transcript_consequences": [
{
"gene_id": "ENSG1",
"gene_symbol": "gene1",
"transcript_id": "ENST1",
"consequence_terms": ["stop_gained"],
"amino_acids": "Q/*",
"biotype": "protein_coding",
"lof": None,
"lof_flags": None,
"canonical": 1,
}
]
},
},
{
"locus": hl.Locus("1", 2000, reference_genome="GRCh37"),
"alleles": ["A", "T"],
"vep": {
"transcript_consequences": [
{
"gene_id": "ENSG2",
"gene_symbol": "gene2",
"transcript_id": "ENST2",
"consequence_terms": ["missense_variant"],
"amino_acids": "K/R",
"biotype": "nonsense_mediated_decay",
"lof": None,
"lof_flags": None,
"canonical": 1,
}
]
},
},
],
hl.tstruct(
locus=hl.tlocus(),
alleles=hl.tarray(hl.tstr),
vep=hl.tstruct(
transcript_consequences=hl.tarray(
hl.tstruct(
gene_id=hl.tstr,
gene_symbol=hl.tstr,
transcript_id=hl.tstr,
consequence_terms=hl.tarray(hl.tstr),
amino_acids=hl.tstr,
biotype=hl.tstr,
lof=hl.tstr,
lof_flags=hl.tstr,
canonical=hl.tint,
)
)
),
),
)


class TestTxFilterVariantsByCsqs:
"""Tests for the tx_filter_variants_by_csqs function."""

def test_filter_to_cds(self, mock_vep_annotated_ht):
"""Test filtering to CDS variants."""
result_ht = tx_filter_variants_by_csqs(
mock_vep_annotated_ht,
filter_to_cds=True,
ignore_splicing=False,
filter_to_protein_coding=False,
)
assert result_ht.count() == 2

def test_filter_to_genes(self, mock_vep_annotated_ht):
"""Test filtering to specific genes."""
result_ht = tx_filter_variants_by_csqs(
mock_vep_annotated_ht,
filter_to_genes=["ENSG1", "ENSG2"],
filter_to_cds=False,
ignore_splicing=False,
filter_to_protein_coding=False,
)
assert result_ht.count() == 2

def test_ignore_splicing(self, mock_vep_annotated_ht):
"""Test ignoring splicing variants."""
result_ht = tx_filter_variants_by_csqs(
mock_vep_annotated_ht,
filter_to_cds=False,
ignore_splicing=True,
filter_to_protein_coding=False,
)
assert result_ht.count() == 4

def test_filter_to_protein_coding(self, mock_vep_annotated_ht):
"""Test filtering to protein coding transcripts."""
result_ht = tx_filter_variants_by_csqs(
mock_vep_annotated_ht,
filter_to_cds=False,
ignore_splicing=False,
filter_to_protein_coding=True,
)
assert result_ht.count() == 4

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