Table 5.

Important correctness differences between the hgvs package and Mutalyzer. The same input variant was provided to hgvs and Mutalyzer (Mutalyzer 2.0.26, released on July 19, 2017)

Feature	Operation	Input Variant	hgvs result	Mutalyzer result	Explanation
indel‐aware projections	Project transcript variant onto aligned genomic sequence	NM_033089.6:c.460C>N NM_033089.6:c.461C>N	NC_000020.10:g.278687C>N NC_000020.10:g.278691C>N	NC_000020.10:g.278687C>N NC_000020.10:g.278688C>N	NM_033089.6 contains a 3‐nucleotide insertion in the genome relative to the transcript between transcript sequence position 484 and 485 (c.460 and c.461), corresponding to g.278687 and g.278691 on NC_000020.10. Mutalyzer will incorrectly compute coordinates after c.484. This issue affects 428 genes and 1104 transcripts in GRCh37, and 131 genes and 336 transcripts in GRCh38.
validate variants before projection	Project transcript variant onto aligned genomic sequence	NM_003002.3:c.500000G>T	Exception raised (“HGVSError: The given coordinate is outside the bounds of the reference sequence.”)	NC_000011.9:g.112465214G>T	hgvs refuses to extrapolate positions beyond the bounds of the sequence alignment. Mutalyzer does not check sequence bounds.
replace reference sequence after projection	Project transcript variant onto aligned genomic sequence	NM_000024.5:c.46A>T	NC_000005.9:g.148206440G>T	NC_000005.9:g.148206440A>T	NM_000024.5:c.46 corresponds to NC_000005.9:g.148206440, the site of a known SNP (rs1042713). The reference nucleotides in the transcript and genomic sequence are A and G respectively. hgvs replaces the genomic reference sequence after projection, while Mutalyzer does not.
normalize variants after projection	Project transcript variant onto aligned genomic sequence	NM_024426.4:c.1137_1141dup	NC_000011.9:g.32417913_32417917dup	NC_000011.9:g.32417911_32417915dup	NM_024426.4 is on the ‐ strand. The input variant is correctly normalized (3′ shifted). After projection to the genomic sequence, the variant can be normalized on the + strand by 2 nucleotides. Mutalyzer appears to not apply normalization after converting positions. https://groups.google.com/forum/#!topic/hgvs-discuss/M8FUdJ-WCDI.
rewrite variants in preferred forms	Normalize/rewrite variant	NM_001166478.1:c.35_36insT	NM_001166478.1:c.35dup	website warning	hgvs rewrites NM_001166478.1:c.35_36insT as NM_001166478.1:c.35dup. Mutalyzer raises a warning but does not correct the error.