Inheritance Annotation

The command jannovar annotate-vcf can also be used for annotating variants with compatible modes of inheritance. For this, you have to specify a pedigree file.

In short, these are TSV files with 6 columns. Each line describes one individual.

  1. Pedigree/family name (only individuals of the first occuring family name are interpreted).
  2. Name of the individual.
  3. Name of the father, 0 for “not in pedigree” (for founders)
  4. Name of the mother, 0 for “not in pedigree” (for founders)
  5. Sex of the individual: 1 for male, 2 for female, 0 for other/unknown
  6. Disease status: 1 for unaffected, 2 for affected, 0 for unknown

Used Pedigree Files

The file ar.ped contains the following pedigree which matches autosomal recessive inheritance. Note that the index could also have a de novo mutation (which is flagged as autosomal dominant by Jannovar).

FAM index   father  mother  1       2
FAM father  0       0       1       1
FAM mother  0       0       2       1

The file ad.ped contains the following pedigree which matches autosomal dominant inheritance.

FAM index   father  mother  1       2
FAM father  0       0       1       2
FAM mother  0       0       2       1

Used VCF File

The flie small.vcf contains the following variant file.

##fileformat=VCFv4.1
##contig=<ID=1,length=249250621>
##INFO=<ID=INHERITANCE,Number=.,Type=String,Description="Mode of Inheritance">
#CHROM      POS     ID      REF     ALT     QUAL    FILTER  INFO    FORMAT  index   father  mother
1   866511  .       C       CCCCT   .       .       .       GT      1/1     0/1     0/1
1   879317  .       C       T       .       .       .       GT      0/1     0/1     0/0
1   879318  .       G       T       .       .       .       GT      0/1     0/0     0/0
1   879482  .       G       C       .       .       .       GT      0/1     0/1     0/0

Note that all variants lie within the same gene, as shown in the following, annotated version of small.vcf.

##fileformat=VCFv4.2
##INFO=<ID=ANN,Number=1,Type=String,Description="Functional annotations:'Allele|Annotation|Annotation_Impact|Gene_Name|Gene_ID|Feature_Type|Feature_ID|Transcript_BioType|Rank|HGVS.c|HGVS.p|cDNA.pos / cDNA.length|CDS.pos / CDS.length|AA.pos / AA.length|Distance|ERRORS / WARNINGS / INFO'">
##INFO=<ID=INHERITANCE,Number=.,Type=String,Description="Mode of Inheritance">
##contig=<ID=1,length=249250621>
##jannovarCommand=annotate-vcf -d data/hg19_refseq.ser -i small.vcf -o small.jv.vcf
##jannovarVersion=0.17
#CHROM      POS     ID      REF     ALT     QUAL    FILTER  INFO    FORMAT  index   father  mother
1   866511  .       C       CCCCT   .       .       ANN=CCCCT|coding_transcript_intron_variant|LOW|SAMD11|148398|transcript|NM_152486.2|Coding|4/13|c.305+42_305+43insCCCT|p.(%3D)|386/18841|306/2046|102/682||     GT      1/1     0/10/1
1   879317  .       C       T       .       .       ANN=T|missense_variant|MODERATE|SAMD11|148398|transcript|XM_005244727.1|Coding|9/9|c.799C>T|p.(Arg267Cys)|1155/19962|799/1188|267/396|| GT      0/1     0/1     0/0
1   879318  .       G       T       .       .       ANN=T|missense_variant|MODERATE|SAMD11|148398|transcript|NM_152486.2|Coding|14/14|c.1831G>T|p.(Val611Leu)|1911/18841|1831/2046|611/682||        GT      0/1     0/0     0/0
1   879482  .       G       C       .       .       ANN=C|missense_variant|MODERATE|SAMD11|148398|transcript|XM_005244727.1|Coding|9/9|c.964G>C|p.(Asp322His)|1320/19962|964/1188|322/396|| GT      0/1     0/0     0/1

Also note that for annotating for compatibility with inheritance, all variants assigned to a gene will be used. This includes deep intronic as well as upstream/downstream (up to 5kbp) variants. Thus, it is a good idea to first filter out low-quality and non-coding variants before annotating compatible modes of inheritance. It remains for future work to include a quality/variant type filter for the pedigree-based filtration.

Annotating AR Variants

The following shows the annotation result with the AR pedigree. The molecular impact annotation ANN is suppressed for brevity.

$ java -jar jannovar-cli.jar annotate-vcf \
    -d data/hg19_refseq.ser -i small.vcf \
    -o small.ar.vcf --pedigree-file ar.ped
$ cat small.ar.vcf
##fileformat=VCFv4.2
##INFO=<ID=ANN,Number=1,Type=String,Description="Functional annotations:'Allele|Annotation|Annotation_Impact|Gene_Name|Gene_ID|Feature_Type|Feature_ID|Transcript_BioType|Rank|HGVS.c|HGVS.p|cDNA.pos / cDNA.length|CDS.pos / CDS.length|AA.pos / AA.length|Distance|ERRORS / WARNINGS / INFO'">
##INFO=<ID=INHERITANCE,Number=.,Type=String,Description="Mode of Inheritance">
##contig=<ID=1,length=249250621>
##jannovarCommand=annotate-vcf -d data/hg19_refseq.ser -i small.vcf -o small.ar.vcf --pedigree-file ar.ped
##jannovarVersion=0.17
#CHROM      POS     ID      REF     ALT     QUAL    FILTER  INFO    FORMAT  index   father  mother
1   866511  .       C       CCCCT   .       .       ANN=[...];INHERITANCE=AR        GT      1/1     0/1     0/1
1   879317  .       C       T       .       .       ANN=[...];INHERITANCE=AR        GT      0/1     0/1     0/0
1   879318  .       G       T       .       .       ANN=[...];INHERITANCE=AD        GT      0/1     0/0     0/0
1   879482  .       G       C       .       .       ANN=[...];INHERITANCE=AR        GT      0/1     0/0     0/1

The variant at

  • chr1:866511 is annotated as compatible with autosomal recessive as it is a “classic” autosomal recessive variant.
  • chr1:879317 is annotated as compatible with autosomal recessive as together with the variant at chr1:879482, it matches the composite autosomal recessive mode of inheritance.
  • chr1:879318 is annotated as compatible with autosomal dominant as it could be a de novo variant that is autosomal dominant.

Annotating AD Variants

$ $ java -jar jannovar-cli.jar annotate-vcf \
    -d data/hg19_refseq.ser -i small.vcf \
    -o small.ad.vcf --pedigree-file ad.ped
$ cat small.ad.vcf
##fileformat=VCFv4.2
##INFO=<ID=ANN,Number=1,Type=String,Description="Functional annotations:'Allele|Annotation|Annotation_Impact|Gene_Name|Gene_ID|Feature_Type|Feature_ID|Transcript_BioType|Rank|HGVS.c|HGVS.p|cDNA.pos / cDNA.length|CDS.pos / CDS.length|AA.pos / AA.length|Distance|ERRORS / WARNINGS / INFO'">
##INFO=<ID=INHERITANCE,Number=.,Type=String,Description="Mode of Inheritance">
##contig=<ID=1,length=249250621>
##jannovarCommand=annotate-vcf -d data/hg19_refseq.ser -i small.vcf -o small.ad.vcf --pedigree-file ad.ped
##jannovarVersion=0.17
#CHROM      POS     ID      REF     ALT     QUAL    FILTER  INFO    FORMAT  index   father  mother
1   866511  .       C       CCCCT   .       .       ANN=[...]       GT      1/1     0/1     0/1
1   879317  .       C       T       .       .       ANN=[...];INHERITANCE=AD        GT      0/1     0/1     0/0
1   879318  .       G       T       .       .       ANN=[...]       GT      0/1     0/0     0/0
1   879482  .       G       C       .       .       ANN=[...];INHERITANCE=AD        GT      0/1     0/1     0/0

The variants at chr1:879317 and chr1:879482 match the autosomal dominant mode of inheritance from the father. The remaining variants do not match this mode of inheritance.

No-calls and Mixed genotypes

We implemented the filter that we might loose specificity but not some sensitibvity.Therfore a genotype call of ./1 or 1/. can be HET or HOM_ALT. 0/. or ./0 are HET or HOM_REF. A no-call of ./. is NO_CALL and will be used only as a wildcard in multi-vcfs but at least one called correct genotype must be observed. For more information see ped_filters.