Question

What is the HGVS notation for the Hemophilia A intron 22 inversion mutation?

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6.9 years ago

bdolin ▴ 90

Greetings,

I'm a bit new to HGVS, but something seems wrong here.

The CDC Hemophilia Mutation Project (CHAMP & CHBMP) site [https://www.cdc.gov/ncbddd/hemophilia/champs.html] contains a spreadsheet which includes HGVS strings for the Hemophilia A intron 22 inversion mutation:

c.6429+?_6430-?h-2inv

c.6429+?_6430-?inv

Neither of these pass the parsing test on [https://mutalyzer.nl/], and they both seem to be only referring to the uncertainty of one end of the inversion.

Does anyone know a different HGVS syntax for this mutation, and/or advice about how to interpret the CDC strings?

Thanks much, Bob

genome gene • 2.6k views

ADD COMMENT • link 6.9 years ago by bdolin ▴ 90

score 0 · Answer 1 · 2017-05-20

c.6429+?_6430-?inv denotes that there is an inversion involving a region extending from an intron downstream of 6429 (from an unknown position within intron) till intronic position (unknown again) upstream of base 6430.

My guess is that there is an intron between positions 6429 and 6430 (6429 being last base of previous exon and 6430 being first base of next exon). There is inversion event within the intron, but intronic base positions (downstream of exon1 and upstream of exon2, in above comment) are unknown.

Till we know exact coordinates of intronic base position, mutalyzer will not give you the result. Btw, c.6429+?_6430-?inv is a valid HGVS syntax.

score 0 · Answer 2 · 2017-05-22

Thank you for your response. I also heard back from a member of the LOVD team, and here is their response:

"the descriptions c.6429+?_6430-?inv and c.6429+?_6430-?h-2inv do not follow current HGVS recommendations. In the F8 gene variant database there is one description of a sequenced F8 inversion; NC_000023.10::g.154116613_154504090inv (see https://databases.lovd.nl/shared/variants/0000170459#00000322). Based on a coding DNA reference sequence LRG_555t1:c.-253263_6429+7739inv. Describing the inversion with unknown breakpoints based on a coding DNA reference sequence is more difficult. LRG_555t1:c.?_(6429+1_6430-1)inv (or NM_000132.3:c.?_(6429+1_6430-1)inv) seem correct, indicating that 1 break point is in intron 22 (c.6429+1_6430-1) and the other at an unknown position 5' of the gene."

score 0 · Answer 3 · 2017-05-23

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Entering edit mode

6.9 years ago

cpad0112 21k

c.6429+?_6430-?inv is a valid HGVS syntax as per mutalyzer HGVS syntax checking tool (https://mutalyzer.nl/syntax-checker), while c.6429+?_6430-?h-2inv is not. Mutalyzer tool checks only for syntax, but doesn't do any biological validation.

ADD COMMENT • link 6.9 years ago by cpad0112 21k

score 0 · Answer 4 · 2017-05-23

Right, but isn't "c.6429+?_6430-?inv" only referring to ONE end of the inversion? It seems to be saying that one end of the inversion is upstream of position 6429 and downstream of position 6430 (i.e. in intron 22). So, you'd need to say something about the other end - perhaps just "1-?" if you know it's upstream of the first exon - something like "c.(1-?)_(6429+?_6430-?)inv"?

score 0 · Answer 5 · 2017-05-25

My understanding, from syntax c.6429+?_6430-?inv, is that:

There is an inversion event
Inversion event is an intronic inversion
The inverted nucleotide stretch has unknown positions within that intron.

Btw, + is downstream and - is upstream. Downstream of 6429 and upstream of 6430 (probable intron).

As per HGVS conventions here (http://varnomen.hgvs.org/recommendations/DNA/variant/inversion/), an inversion syntax format is:

Format: “prefix”“positions_inverted”“inv”, e.g. g.123_345inv (copy/pasted)

In case of c.6429+?_6430-?inv,

Prefix=c (coding)
Position 1= 6429+? (downstream of 6429, but unknown position, 6429 being coding) (equivalent to 123 in g.123_345inv)
Position 2 = 6430-? (Upstream 0f 6430, but unknown position, 6430 being coding) (equivalent to 345 in g.123_345inv)
inv= inversion event

A related, but good example from HGVS site is: chrX:g.(?_32238146)_(32984039_?)del

In this case, deletion started from somewhere (unknown position) upstream of 32238146 and ended somewhere (unknown) downstream of 32984039.

If it were inversion, it would be chrX:g.(?_32238146)_(32984039_?)inv

score 0 · Answer 6 · 2017-05-25

Thanks for your comments. The Hemophilia A intron 22 inversion is well described in the literature - here is a quote: "It is hypothesized that the inversion mutations occur almost exclusively in germ cells during meiotic cell division by an intrachromosomal recombination between a 9.6-kb sequence within intron 22 and 1 of 2 almost identical copies located about 300 kb distal to the factor VIII gene at the telomeric end of the X chromosome".

Meanwhile, I also heard back from the CDC, and here is their response:

[Question #1] I'm not following your HGVS syntax for intron22 inversions. For instance, you have [c.6429+?_6430-?h-2inv] and c.6429+?_6430-?inv], neither of which parse correctly here [https://mutalyzer.nl/]. I'm a bit new to HGVS, but your expression appears to only show one end of the inversion? Please help me understand what these strings are saying.

[CDC Response to #1] While we use HGVS nomenclature standards, the standards are frequently changing – particularly for complex rearrangements. The nomenclature we use reflects that the inversion involves intron 22 (c.6429+1_6430-1) but that the exact break points within intron 22 are unmapped (hence the ‘?’). Furthermore, we capture the differences between Type 1, Type 2, and atypical intron 22 inversions. Type 1 inversions occur when there is intrachromosomal rearrangement between a region inside intron 22 (h-1) and a homologous region outside the F8 gene (h-3) – these would be called c.6429+?_6430-?h-3inv in our database. Type 2 inversions occur when there is intrachromosomal rearrangement between h-1 and a second homologous region outside the F8 gene (h-2) – these would be called c.6429+?_6430-?h-2inv in our database. The rearrangement pattern is unclear for atypical intron 22 inversions – these would be called c.6429+?_6430-?inv.

[Question #2] I don't see these mutations registered in ClinVar or dbVar. Will they be? The intron22 inversion can be found in ClinVar by a search "hemophilia f8 inversion", but not by an HGVS search; and I don't find anything in dbVar.

[CDC Response to #2] The variant referenced in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/10150/) appears to be generic reference to the Intron 22 inversion. Because HGVS nomenclature standards change frequently for complex rearrangements, the HGVS name would probably not be the best search mechanism to identify other reports of intron 22 inversions in these large databases. Because the intron 22 inversions have been studied for many years, a more productive search would be to search the literature with historical nomenclature (Intron 22 Type 1 inversion, Intron 22 Type 2 inversion, etc.).

So, I feel like HGVS syntax should be something like (6429+?)_(1-?)inv, where the "(1-?)" indicates that the other end of the inverted segment is an unknown distance 5' from the start of the first position of the first exon.