Examples

This section shows how SvAnna prioritizes various structural variant classes. The resulting HTML reports contain graphics that are reported in the supplement of SvAnna paper.

The examples work with variants stored in examples.vcf file. The VCF file is stored in SvAnna GitHub repository. Use the run_examples.sh script to generate HTML reports for all cases described below. Note that you must enter the paths to SvAnna JAR file, data directory, and the examples.vcf into the script before running.

Single exon deletion

A deletion of 6.93 kb (chr17:31,150,798-31,157,725del) affecting NF1 that was assigned a PSV score of 124.98.

The deletion affects exon 2 of several NF1 transcripts. Pathogenic variants in NF1 are associated with neurofibromatosis type 1 (OMIM:162200).

The phenotypic features curated for the proband UAB-1 were:

HP:0007565 Multiple cafe-au-lait spots
HP:0009732 Plexiform neurofibroma
HP:0009735 Spinal neurofibromas
HP:0009736 Tibial pseudarthrosis

Data were curated from a published case report in Decoding NF1 Intragenic Copy-Number Variations.

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    -t HP:0007565 \
    -t HP:0009732 \
    -t HP:0009735 \
    -t HP:0009736

Deletion of multiple exons

A deletion of 10.26 kb (chr17:43,100,079-43,110,335del) affecting BRCA1 that was assigned a PSV score of 272.91.

The deletion affects three BRCA1 exons. Pathogenic variants in BRCA1 are associated with Breast-ovarian cancer, familial, 1 (OMIM:604370).

The phenotypic feature curated for this case was:

HP:0003002 Breast carcinoma

Data were curated from a published case report The first case report of a large deletion of the BRCA1 gene in Croatia.

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0003002

Deletion of multiple genes

Deletion of 481.73 kb (chr2:109,923,337-110,405,062del) affecting MALL, NPHP1, and MTLN that was assigned a PSV score of 16.41.

Pathogenic variants in NPHP1 are associated with Joubert syndrome 4 (OMIM:609583).

The phenotypic features curated for this case were:

HP:0003774 Stage 5 chronic kidney disease
HP:0001320 Cerebellar vermis hypoplasia
HP:0002078 Truncal ataxia
HP:0000618 Blindness
HP:0000508 Ptosis
HP:0002419 Molar tooth sign on MRI
HP:0011933 Elongated superior cerebellar peduncle
HP:0002070 Limb ataxia
HP:0000543 Optic disc pallor
HP:0000589 Coloboma

Data were curated from a published case report Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders.

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0003774 \
    --phenotype-term HP:0001320 \
    --phenotype-term HP:0002078 \
    --phenotype-term HP:0000618 \
    --phenotype-term HP:0000508 \
    --phenotype-term HP:0002419 \
    --phenotype-term HP:0011933 \
    --phenotype-term HP:0002070 \
    --phenotype-term HP:0000543 \
    --phenotype-term HP:0000589

Duplication of coding sequence

Duplication of 36 bp (chr13:72835296-72835332dup) affecting PIBF1 that was assigned a PSV score of 3.29. Pathogenic variants in PIBF1 are associated with Joubert syndrome 33 (OMIM:617767).

The phenotypic features curated for this case were:

HP:0032417 Periglomerular fibrosis
HP:0000076 Vesicoureteral reflux
HP:0002079 Hypoplasia of the corpus callosum
HP:0001541 Ascites
HP:0000540 Hypermetropia
HP:0011968 Feeding difficulties
HP:0001250 Seizure
HP:0000490 Deeply set eye
HP:0001263 Global developmental delay
HP:0001284 Areflexia
HP:0002240 Hepatomegaly
HP:0001290 Generalized hypotonia
HP:0031200 Hyaline casts
HP:0011800 Midface retrusion
HP:0000090 Nephronophthisis
HP:0000092 Renal tubular atrophy
HP:0001919 Acute kidney injury
HP:0012650 Perisylvian polymicrogyria
HP:0002419 Molar tooth sign on MRI
HP:0002119 Ventriculomegaly
HP:0000105 Enlarged kidney

Data were curated from a published case report A biallelic 36-bp insertion in PIBF1 is associated with Joubert syndrome

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0032417 \
    --phenotype-term HP:0000076 \
    --phenotype-term HP:0002079 \
    --phenotype-term HP:0001541 \
    --phenotype-term HP:0000540 \
    --phenotype-term HP:0011968 \
    --phenotype-term HP:0001250 \
    --phenotype-term HP:0000490 \
    --phenotype-term HP:0001263 \
    --phenotype-term HP:0001284 \
    --phenotype-term HP:0002240 \
    --phenotype-term HP:0001290 \
    --phenotype-term HP:0031200 \
    --phenotype-term HP:0011800 \
    --phenotype-term HP:0000090 \
    --phenotype-term HP:0000092 \
    --phenotype-term HP:0001919 \
    --phenotype-term HP:0012650 \
    --phenotype-term HP:0002419 \
    --phenotype-term HP:0002119 \
    --phenotype-term HP:0000105

Multigene inversion

Inversion of ~12.23 kb (inv(chr3)(9725702; 9737931)) that disrupts the coding sequence of BRPF1 was assigned PSV score of 8.01.

Pathogenic variants in BRPF1 are associated with Intellectual developmental disorder with dysmorphic facies and ptosis OMIM:617333.

The phenotypic features curated for this case were:

HP:0000316 Hypertelorism
HP:0000494 Downslanted palpebral fissures
HP:0000431 Wide nasal bridge
HP:0000286 Epicanthus
HP:0000311 Round face
HP:0012368 Flat face
HP:0000486 Strabismus
HP:0000508 Ptosis
HP:0002949 Fused cervical vertebrae
HP:0002194 Delayed gross motor development
HP:0000750 Delayed speech and language development
HP:0002342 Intellectual disability, moderate
HP:0011150 Myoclonic absence seizure
HP:0002069 Bilateral tonic-clonic seizure
HP:0001252 Hypotonia

Data were curated from a published case report Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0000286 \
    --phenotype-term HP:0002069 \
    --phenotype-term HP:0000494 \
    --phenotype-term HP:0002342 \
    --phenotype-term HP:0000486 \
    --phenotype-term HP:0000750 \
    --phenotype-term HP:0000431 \
    --phenotype-term HP:0001252 \
    --phenotype-term HP:0002194 \
    --phenotype-term HP:0012368 \
    --phenotype-term HP:0011150 \
    --phenotype-term HP:0002949 \
    --phenotype-term HP:0000508 \
    --phenotype-term HP:0000316 \
    --phenotype-term HP:0000311

Deletion affecting transcription start site

Deletion of ∼1.57 kb (chrX:64,205,190-64,206,761del) affecting transcription start site of AMER1 was assigned PSV score of 9.05.

Pathogenic variants in AMER1 are associated with Osteopathia striata with cranial sclerosis (OMIM:300373).

The phenotypic features curated for this case were:

HP:0001561 Polyhydramnios
HP:0002684 Thickened calvaria
HP:0000256 Macrocephaly
HP:0000316 Hypertelorism
HP:0031367 Metaphyseal striations
HP:0002744 Bilateral cleft lip and palate
HP:0002781 Upper airway obstruction
HP:0001004 Lymphedema
HP:0000750 Delayed speech and language development

Data were curated from a published case report Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis.

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0001561 \
    --phenotype-term HP:0000750 \
    --phenotype-term HP:0002684 \
    --phenotype-term HP:0002781 \
    --phenotype-term HP:0000316 \
    --phenotype-term HP:0031367 \
    --phenotype-term HP:0002744 \
    --phenotype-term HP:0000256 \
    --phenotype-term HP:0001004

Deletion affecting promoter region

A deletion of 13 bp (chr12:6,124,705-6,124,718del) located in the core promoter region of VWF was assigned PSV score of 47.26.

In the original publication, the deletion was shown to lead to aberrant binding of Ets transcription factors to the site of the deletion (30 bp upstream of ENST00000261405.10) and thereby reduce VWF expression.

Pathogenic variants in VWF are associated with von Willebrand disease (OMIM:193400).

The phenotypic features curated for this case were:

HP:0011890 Prolonged bleeding following procedure
HP:0000978 Bruising susceptibility
HP:0012147 Reduced quantity of Von Willebrand factor

Data were curated from a published case report Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease.

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    --vcf example.vcf \
    --phenotype-term HP:0011890 \
    --phenotype-term HP:0000978 \
    --phenotype-term HP:0012147

Translocation disrupting a gene sequence

A translocation (t(chr3:11,007,014; chr4:139,383,334)) affecting SLC6A1 was assigned PSV score of 4.51.

Pathogenic variants in SLC6A1 are associated with Myoclonic-atonic epilepsy (OMIM:616421).

The phenotypic features curated for this case were:

HP:0000252 Microcephaly
HP:0000446 Narrow nasal bridge
HP:0000272 Malar flattening
HP:0000219 Thin upper lip vermilion
HP:0000179 Thick lower lip vermilion
HP:0002650 Scoliosis
HP:0002987 Elbow flexion contracture
HP:0006380 Knee flexion contracture
HP:0001250 Seizure
HP:0001263 Global developmental delay
HP:0001276 Hypertonia

Data were curated from a published case report Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15

Command

$ java -jar svanna-cli.jar prioritize \
    -d path/to/svanna-data \
    -vcf example.vcf \
    --phenotype-term HP:0000252 \
    --phenotype-term HP:0000446 \
    --phenotype-term HP:0000272 \
    --phenotype-term HP:0000219 \
    --phenotype-term HP:0000179 \
    --phenotype-term HP:0002650 \
    --phenotype-term HP:0002987 \
    --phenotype-term HP:0006380 \
    --phenotype-term HP:0001250 \
    --phenotype-term HP:0001263 \
    --phenotype-term HP:0001263 \
    --phenotype-term HP:0001276