Technical interview guide

Variant Calling & Genomic File Formats

The FASTQ-to-VCF pipeline — how raw reads become a filtered list of called variants, and the file formats each stage produces.

Read: 50 min
Practice MCQs: 25
Interview QA: 25
Edition: v4
Editorial status: Reviewed
Relevant for: Computational Biologist

Scope: VCF 4.5 / BCF 2.2, SAM/BAM and CRAM 3.1 specifications; current GATK, bcftools, samtools, GIAB, vcfeval and GA4GH VRS guidance reviewed 2026-09-04.

Interview QA

Treat each question like a live interview question: answer out loud first (structure, assumptions, tradeoffs), then open the model answer to spot gaps and rehearse a tighter follow-up.

Curated: 2026-10-05 · Written: 2026-10-05 · Reviewed: 2026-10-04

QA-1

Validate reference compatibility before merging calls.

QA-2

Audit sequencing quality before calling.

QA-3

Archive alignment data in CRAM safely.

QA-4

Parse alignments without coordinate errors.

QA-5

Set mapping evidence policy for calling.

QA-6

Choose duplicate handling for an assay.

QA-7

Apply BQSR to a non-model organism.

QA-8

Diagnose a missed indel in a haplotype caller.

QA-9

Choose a tumor-normal calling strategy.

QA-10

Interpret PL and GQ fields.

QA-11

Call variants across sex chromosomes.

QA-12

Design cohort joint genotyping.

QA-13

Convert VCF records to intervals safely.

QA-14

Parse VCF sample fields robustly.

QA-15

Normalize multiallelic calls without corrupting evidence.

QA-16

Build a VCF ingestion quality gate.

QA-17

Normalize a VCF for comparison.

QA-18

Choose a variant-filtering approach.

QA-19

Parse structural-variant records.

QA-20

Use phased calls in compound-heterozygous analysis.

QA-21

Validate a copy-number pipeline.

QA-22

Design a re-annotatable variant store.

QA-23

Benchmark a germline caller against GIAB.

QA-24

How do you distinguish between missing data, reference homozygous, and uncalled regions across multi-sample cohorts using gVCF representation and the non-variant block mechanism?

QA-25