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Clinical-Genomics / scout

VCF visualization interface
https://clinical-genomics.github.io/scout
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Causative variants not called #4086

Closed MUebe closed 1 year ago

MUebe commented 1 year ago

Hi! We noted an issue with calling variants in case 23036. The previously causative variant in APRT is not called in any of the two individuals, even though I can see it when I look manually in IGV. Would be good to find out why, and if this also might happen in other cases. Kind regards, Malin

MUebe commented 1 year ago

Correction: the problematic case is called 23036-duo.

northwestwitch commented 1 year ago

From the answer of @jemten to a ticket relative to the same issue:

Hello,

Looks like the rankscore for this variant has dropped to 5 and it is thus no longer loaded into scout. This is due to the gene having a AR inheritance pattern and the new sample is marked as affected but is only heterozygot for that variant. As it doesn't follow the inheritance pattern it get's penalised in the rankmodel with a -12.

kind regards,

Anders
dnil commented 1 year ago

Hi, that is unfortunate! I believe this is best adressed in the setting of the pipeline or possibly genmod/rankmodel - or possibly the order system.

The very simple answer is that being a splice variant in multiple overlapping genes, the score was not super fantastic before, but high enough, 18 in model 1.34, but really plummeted to 5 in the duo with 1.35, pushing it below the load threshold.

The salient difference is going from 1 to -12 on inheritance model. I will say the inheritance pattern is currently unclear to me as well: I see no pedigree, and two affected individuals but one heterozygous and one homozygous for the purported mutation. If you explain how the patient status and anamnesis is in fact, perhaps we can move to see how it was propagated through the system?

Variants for reference below

Singleton:

##INFO=<ID=RankResult,Number=.,Type=String,Description="allele_frequency|protein_prediction|gene_intolerance_prediction|inheritance_models|consequence|conservation|variant_call_quality_filter|deleteriousness|clinical_significance|splicing">

RankScore=brightoryx:18;RankResult=3|0|0|1|5|0|3|3|0|3

16  88876831    16_88876831_C_T C   T   61  .   CSQ=T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000268695|protein_coding|||||||||||3311|-1||HGNC|4122|YES|||CCDS10970.1|ENSP00000268695|GALNS_HUMAN|Q96I49_HUMAN&Q6YL38_HUMAN|UPI000012AF92|||Ensembl||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000301019|protein_coding|||||||||||1165|1||HGNC|24576|YES|||CCDS32510.1|ENSP00000301019|CDT1_HUMAN||UPI00001FF6B1|||Ensembl||C|C||||||||||||||||||0.757|0.00|||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000378364|protein_coding|3/5||ENST00000378364.3:c.321G>A|ENSP00000367615.3:p.Lys107%3D|366|321|107|K|aaG/aaA|||-1||HGNC|626|YES|||CCDS32511.1|ENSP00000367615|APT_HUMAN|H3BSW3_HUMAN|UPI0000161B16|||Ensembl||C|C||||HAMAP:MF_00004&PANTHER:PTHR32315&Pfam:PF00156&TIGRFAM:TIGR01090&Gene3D:3.40.50.2020&Superfamily:SSF53271||||||||||||||0.271|0.00|6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000426324|protein_coding|3/5||ENST00000426324.2:c.321G>A|ENSP00000397007.2:p.Lys107%3D|347|321|107|K|aaG/aaA|||-1||HGNC|626||||CCDS45546.1|ENSP00000397007|APT_HUMAN|H3BSW3_HUMAN|UPI0000576838|||Ensembl||C|C||||PANTHER:PTHR32315&Pfam:PF00156&Gene3D:3.40.50.2020&Superfamily:SSF53271||||||||||||||0.271|0.00|6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000542788|protein_coding|||||||||||3312|-1||HGNC|4122|||||ENSP00000438197||Q96I49_HUMAN&Q6YL38_HUMAN&F5H325_HUMAN|UPI000206585B|||Ensembl||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|intron_variant&non_coding_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000562464|retained_intron||1/2|ENST00000562464.1:n.332-275G>A|||||||||-1||HGNC|626|||||||||||Ensembl||C|C||||||||||||||||||0.271|0.00|6.568|8.366||2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000562593|retained_intron|||||||||||3312|-1||HGNC|4122|||||||||||Ensembl||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000562747|retained_intron|||||||||||4206|1||HGNC|24576|||||||||||Ensembl||C|C||||||||||||||||||0.757|0.00|||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|intron_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000563655|protein_coding||2/3|ENST00000563655.1:c.241-275G>A|||||||||-1||HGNC|626|||||ENSP00000456012||H3BSW3_HUMAN&H3BQZ9_HUMAN|UPI00024671F8|||Ensembl||C|C||||||||||||||||||0.271|0.00|6.568|8.366|5.660|-7.129|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000564858|retained_intron|||||||||||751|-1||HGNC|626|||||||||||Ensembl||C|C||||||||||||||||||0.271|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|upstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000567057|retained_intron|||||||||||155|-1||HGNC|626|||||||||||Ensembl||C|C||||||||||||||||||0.271|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|intron_variant&NMD_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000567391|nonsense_mediated_decay||2/3|ENST00000567391.1:c.188-275G>A|||||||||-1||HGNC|626|||||ENSP00000457964||H3BSW3_HUMAN|UPI00024671F7|||Ensembl||C|C||||||||||||||||||0.271|0.00|6.568|8.366|5.660|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000567525|nonsense_mediated_decay|||||||||||3313|-1|cds_start_NF|HGNC|4122|||||ENSP00000454484||Q6MZF5_HUMAN|UPI00001BDF3D|||Ensembl||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000567713|protein_coding|3/4||ENST00000567713.1:c.321G>A|ENSP00000455749.1:p.Lys107%3D|345|321|107|K|aaG/aaA|||-1|cds_end_NF|HGNC|626|||||ENSP00000455749||H3BSW3_HUMAN&H3BQF1_HUMAN|UPI00024671F6|||Ensembl||C|C||||PANTHER:PTHR32315&Gene3D:3.40.50.2020&Pfam:PF00156&Superfamily:SSF53271||||||||||||||0.271|0.00|-6.281|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|intron_variant&NMD_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000568319|nonsense_mediated_decay||2/3|ENST00000568319.1:c.188-275G>A|||||||||-1||HGNC|626|||||ENSP00000456905||H3BSW3_HUMAN|UPI00024671F7|||Ensembl||C|C||||||||||||||||||0.271|0.00|6.568|8.366|5.660|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|upstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000568575|retained_intron|||||||||||25|-1||HGNC|626|||||||||||Ensembl||C|C||||||||||||||||||0.271|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000568613|nonsense_mediated_decay|||||||||||3900|-1|cds_start_NF|HGNC|4122|||||ENSP00000457921||H3BV24_HUMAN|UPI00024671FA|||Ensembl||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000569140|protein_coding|||||||||||3081|1|cds_start_NF&cds_end_NF|HGNC|24576|||||ENSP00000456926|||UPI00024671F5|||Ensembl||C|C||||||||||||||||||0.757|0.00|||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000569616|protein_coding|3/5||ENST00000569616.1:c.321G>A|ENSP00000455692.1:p.Lys107%3D|319|321|107|K|aaG/aaA|||-1|cds_start_NF|HGNC|626|||||ENSP00000455692|||UPI00024671F9|||Ensembl||C|C||||PANTHER:PTHR32315&Gene3D:3.40.50.2020&Pfam:PF00156&Superfamily:SSF53271||||||||||||||0.271|0.00|6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|353|Transcript|NM_000485.3|protein_coding|3/5||NM_000485.3:c.321G>A|NP_000476.1:p.Lys107%3D|350|321|107|K|aaG/aaA|||-1||EntrezGene|626|YES||||NP_000476.1||||||RefSeq||C|C||||||||||||||||||0.271|0.00|6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_000512.5|protein_coding|||||||||||3311|-1||EntrezGene|4122|||||NP_000503.1||||||RefSeq||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|353|Transcript|NM_001030018.2|protein_coding|3/5||NM_001030018.2:c.321G>A|NP_001025189.1:p.Lys107%3D|350|321|107|K|aaG/aaA|||-1||EntrezGene|626|||||NP_001025189.1||||||RefSeq||C|C||||||||||||||||||0.271|0.00|6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_001323543.2|protein_coding|||||||||||3311|-1||EntrezGene|4122|||||NP_001310472.1||||||RefSeq||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_001323544.2|protein_coding|||||||||||3311|-1||EntrezGene|4122|YES||||NP_001310473.1||||||RefSeq||C|C||||||||||||||||||0.0838|0.00|||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|downstream_gene_variant|MODIFIER|CDT1|81620|Transcript|NM_030928.4|protein_coding|||||||||||1165|1||EntrezGene|24576|YES||||NP_112190.2||||||RefSeq||C|C||||||||||||||||||0.757|0.00|||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT|||||,T|regulatory_region_variant|MODIFIER|||RegulatoryFeature|ENSR00000089591|promoter|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||;AQ=61;AZTYPE=ND;Frq=0.00028;AZMARKERS=1596;AZ;Obs=2;CADD=23.1;GNOMADAF_popmax=6.4868e-05;AF=1;AZQUAL=93.0;SPIDEX=-1.968;GNOMADAF=3.1861e-05;AZLENGTH=1464196;FOUND_IN=deepvariant;most_severe_consequence=626:T|splice_region_variant,24576:T|downstream_gene_variant,4122:T|downstream_gene_variant;Annotation=GALNS,APRT;GeneticModels=brightoryx:AR_hom;ModelScore=brightoryx:59;RankScore=brightoryx:18;RankResult=3|0|0|1|5|0|3|3|0|3  GT:DP:AD:GQ:PL:RNC  1/1:40:0,40:59:61,62,0:..

Duo

##INFO=<ID=RankResult,Number=.,Type=String,Description="allele_frequency|protein_prediction|gene_intolerance_prediction|inheritance_models|consequence|conservation|variant_call_quality_filter|deleteriousness|clinical_significance|splicing">
RankResult=3|0|0|-12|5|0|3|3|0|3
16  88876831    16_88876831_C_T C   T   70  .   CSQ=T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000268695|protein_coding|||||||||||3311|-1||HGNC|4122|YES|||CCDS10970.1|ENSP00000268695|GALNS_HUMAN|Q96I49_HUMAN&Q6YL38_HUMAN|UPI000012AF92|||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000301019|protein_coding|||||||||||1165|1||HGNC|24576|YES|||CCDS32510.1|ENSP00000301019|CDT1_HUMAN||UPI00001FF6B1|||Ensembl||C|C|||||||||||||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.757|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000378364|protein_coding|3/5||ENST00000378364.3:c.321G>A|ENSP00000367615.3:p.Lys107%3D|366|321|107|K|aaG/aaA|||-1||HGNC|626|YES|||CCDS32511.1|ENSP00000367615|APT_HUMAN|H3BSW3_HUMAN|UPI0000161B16|||Ensembl||C|C||||HAMAP:MF_00004&PANTHER:PTHR32315&Pfam:PF00156&TIGRFAM:TIGR01090&Gene3D:3.40.50.2020&Superfamily:SSF53271|||||||6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000426324|protein_coding|3/5||ENST00000426324.2:c.321G>A|ENSP00000397007.2:p.Lys107%3D|347|321|107|K|aaG/aaA|||-1||HGNC|626||||CCDS45546.1|ENSP00000397007|APT_HUMAN|H3BSW3_HUMAN|UPI0000576838|||Ensembl||C|C||||PANTHER:PTHR32315&Pfam:PF00156&Gene3D:3.40.50.2020&Superfamily:SSF53271|||||||6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000542788|protein_coding|||||||||||3312|-1||HGNC|4122|||||ENSP00000438197||Q96I49_HUMAN&Q6YL38_HUMAN&F5H325_HUMAN|UPI000206585B|||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|intron_variant&non_coding_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000562464|retained_intron||1/2|ENST00000562464.1:n.332-275G>A|||||||||-1||HGNC|626|||||||||||Ensembl||C|C|||||||||||6.568|8.366||2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000562593|retained_intron|||||||||||3312|-1||HGNC|4122|||||||||||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000562747|retained_intron|||||||||||4206|1||HGNC|24576|||||||||||Ensembl||C|C|||||||||||||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.757|||||,T|intron_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000563655|protein_coding||2/3|ENST00000563655.1:c.241-275G>A|||||||||-1||HGNC|626|||||ENSP00000456012||H3BSW3_HUMAN&H3BQZ9_HUMAN|UPI00024671F8|||Ensembl||C|C|||||||||||6.568|8.366|5.660|-7.129|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000564858|retained_intron|||||||||||751|-1||HGNC|626|||||||||||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|upstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000567057|retained_intron|||||||||||155|-1||HGNC|626|||||||||||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|intron_variant&NMD_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000567391|nonsense_mediated_decay||2/3|ENST00000567391.1:c.188-275G>A|||||||||-1||HGNC|626|||||ENSP00000457964||H3BSW3_HUMAN|UPI00024671F7|||Ensembl||C|C|||||||||||6.568|8.366|5.660|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000567525|nonsense_mediated_decay|||||||||||3313|-1|cds_start_NF|HGNC|4122|||||ENSP00000454484||Q6MZF5_HUMAN|UPI00001BDF3D|||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000567713|protein_coding|3/4||ENST00000567713.1:c.321G>A|ENSP00000455749.1:p.Lys107%3D|345|321|107|K|aaG/aaA|||-1|cds_end_NF|HGNC|626|||||ENSP00000455749||H3BSW3_HUMAN&H3BQF1_HUMAN|UPI00024671F6|||Ensembl||C|C||||PANTHER:PTHR32315&Gene3D:3.40.50.2020&Pfam:PF00156&Superfamily:SSF53271|||||||-6.281|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|intron_variant&NMD_transcript_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000568319|nonsense_mediated_decay||2/3|ENST00000568319.1:c.188-275G>A|||||||||-1||HGNC|626|||||ENSP00000456905||H3BSW3_HUMAN|UPI00024671F7|||Ensembl||C|C|||||||||||6.568|8.366|5.660|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|upstream_gene_variant|MODIFIER|APRT|ENSG00000198931|Transcript|ENST00000568575|retained_intron|||||||||||25|-1||HGNC|626|||||||||||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|ENSG00000141012|Transcript|ENST00000568613|nonsense_mediated_decay|||||||||||3900|-1|cds_start_NF|HGNC|4122|||||ENSP00000457921||H3BV24_HUMAN|UPI00024671FA|||Ensembl||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|downstream_gene_variant|MODIFIER|CDT1|ENSG00000167513|Transcript|ENST00000569140|protein_coding|||||||||||3081|1|cds_start_NF&cds_end_NF|HGNC|24576|||||ENSP00000456926|||UPI00024671F5|||Ensembl||C|C|||||||||||||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.757|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|ENSG00000198931|Transcript|ENST00000569616|protein_coding|3/5||ENST00000569616.1:c.321G>A|ENSP00000455692.1:p.Lys107%3D|319|321|107|K|aaG/aaA|||-1|cds_start_NF|HGNC|626|||||ENSP00000455692|||UPI00024671F9|||Ensembl||C|C||||PANTHER:PTHR32315&Gene3D:3.40.50.2020&Pfam:PF00156&Superfamily:SSF53271|||||||6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|353|Transcript|NM_000485.3|protein_coding|3/5||NM_000485.3:c.321G>A|NP_000476.1:p.Lys107%3D|350|321|107|K|aaG/aaA|||-1||EntrezGene|626|YES||||NP_000476.1||||||RefSeq||C|C|||||||||||6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_000512.5|protein_coding|||||||||||3311|-1||EntrezGene|4122|||||NP_000503.1||||||RefSeq||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|splice_region_variant&synonymous_variant|LOW|APRT|353|Transcript|NM_001030018.2|protein_coding|3/5||NM_001030018.2:c.321G>A|NP_001025189.1:p.Lys107%3D|350|321|107|K|aaG/aaA|||-1||EntrezGene|626|||||NP_001025189.1||||||RefSeq||C|C|||||||||||6.568|10.567|9.235|2.919|-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567|6.913|3.654|10.567|10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.271|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_001323543.2|protein_coding|||||||||||3311|-1||EntrezGene|4122|||||NP_001310472.1||||||RefSeq||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|downstream_gene_variant|MODIFIER|GALNS|2588|Transcript|NM_001323544.2|protein_coding|||||||||||3311|-1||EntrezGene|4122|YES||||NP_001310473.1||||||RefSeq||C|C|||||||||||||||-10.077|-7.955|-5.628|-18.032|6.913|3.654|10.567|10.567||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.0838|||||,T|downstream_gene_variant|MODIFIER|CDT1|81620|Transcript|NM_030928.4|protein_coding|||||||||||1165|1||EntrezGene|24576|YES||||NP_112190.2||||||RefSeq||C|C|||||||||||||||8.258|0.034|8.292|8.292|-9.267|0.864|-8.402|-8.402||||10|40|10|0|0.00|0.00|0.33|0.24|APRT||||||||0.00|0.757|||||,T|regulatory_region_variant|MODIFIER|||RegulatoryFeature|ENSR00000089591|promoter|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||;Frq=0.00032;Hom=1;FOUND_IN=deepvariant;GNOMADAF_popmax=6.4868e-05;Obs=3;CADD=23.1;AQ=70;AF=0.75;SPIDEX=-1.968;GNOMADAF=3.1861e-05;most_severe_consequence=24576:T|downstream_gene_variant,626:T|splice_region_variant,4122:T|downstream_gene_variant;Annotation=GALNS,APRT;RankScore=usefulpython:5;RankResult=3|0|0|-12|5|0|3|3|0|3    GT:DP:AD:GQ:PL:RNC  1/1:40:0,40:67:70,70,0:..   0/1:46:22,24:41:40,0,59:..
dnil commented 1 year ago

And one more thing, if you already have a ticket submitted, perhaps wait a little with submitting an issue, or vice versa, to avoid duplication of effort. Thanks! 😸

MUebe commented 1 year ago

Hi again! I am very sorry about the double effort. The reason we got alarmed was because we would have expected the variant to at least be displayed as matching causative. But I can see now that assuming both individuals are affected, the rank will be very low. Does that mean even variants that were marked causative previously will not be displayed if they get ranked below the load threshold?

northwestwitch commented 1 year ago

Hi again! I am very sorry about the double effort. The reason we got alarmed was because we would have expected the variant to at least be displayed as matching causative. But I can see now that assuming both individuals are affected, the rank will be very low. Does that mean even variants that were marked causative previously will not be displayed if they get ranked below the load threshold?

Yes, that's what happened in this case. Unless the variant is in the list of the managed ones.

dnil commented 1 year ago

But that is an excellent point - it would not cost a lot to flag also old causatives for loading together with ClinVar variants and Managed variants. Even if we still want to keep encouraging variant submission to ClinVar, which should have solved this? Perhaps the annotation db was not updated since the discovery of the variant?

northwestwitch commented 1 year ago

Closing this PR, as the question has been answered