rs80357868
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.3756_3759del(p.Ser1253ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1252L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 frameshift
NM_007294.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.02
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 17-43091771-TAGAC-T is Pathogenic according to our data. Variant chr17-43091771-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 17673.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091771-TAGAC-T is described in Lovd as [Pathogenic]. Variant chr17-43091771-TAGAC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA1 | NM_007294.4 | c.3756_3759del | p.Ser1253ArgfsTer10 | frameshift_variant | 10/23 | ENST00000357654.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 | ENST00000357654.9 | c.3756_3759del | p.Ser1253ArgfsTer10 | frameshift_variant | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251272Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135786
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GnomAD4 genome 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:50
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:23
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1994 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jan 07, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 19, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 25, 2020 | The BRCA1 c.3756_3759delGTCT variant is classified as Pathogenic (PVS1, PM2, PP5_Moderate) This BRCA1 c.3756_3759delGTCT variant is predicted to cause a shift in the reading frame at codon 1253, introducing a premature termination codon (PVS1). The variant has been reported in dbSNP (rs80357868) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17673). It has not been reported in HGMD. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Nov 01, 2017 | The c.3756_3759delGTCT (p.Ser1253Argfs*10) frame shift variant is predicted to yield loss of function transcripts/proteins of BRCA1 gene, which is one of mechanisms causing BRCA1 defect related cancers. This variant is extremely rare in general population (4 in 246010 by gnomad) and observed in multiple breast/ovarian cancer patients (PMID:78944991, 12947551, 21324516, 23633455, 24504028). It has been also observed in other clinical labs and reported as pathogenic. Based on the above evidences, we interpret this variant as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Feb 10, 2015 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jun 25, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 24, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 09, 2022 | _x000D_ Criteria applied: PVS1, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 11, 2023 | This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 08, 2023 | The BRCA1 c.3756_3759del (p.Ser1253Argfs*10) variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 33471991 (2021), 29339979 (2018), 11183185 (2000), 8531967 (1996)), ovarian cancer (PMID: 33287145 (2020), 30078507 (2018), 21324516 (2011)), and pancreatic cancer (PMID: 21989927 (2012)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010)). The frequency of this variant in the general population, 0.000044 (5/113572 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21324516, 23621881, 24504028, 27533253, 29310832, 23199084, 31447099, 12947551, 7894491, 23633455, 22711857, 21989927, 27003155, 26779294, 22864640, 25085752, 27356891, 27836010, 27225819, 26843898, 27157322, 27383479, 27062684, 29339979, 28724667, 28423363, 28176296, 30702160, 30720243, 30535581, 31090900, 31159747, 30078507, 30128899, 30103829, 30322717, 26681312, 30093976, 30972954, 31472684, 32388397) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 13, 2019 | PVS1, PS4_Mod, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 09, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | BRCA1: PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 22, 2016 | Variant summary: The BRCA1 c.3756_3759delGTCT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln1756fs). Mutation Taster predicts a damaging outcome for this variant. This variant was found in 3/121438 control chromosomes at a frequency of 0.0000247, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant has been cited in multiple HBOC patients in the literature. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 08, 2019 | The p.Ser12353ArgfsX10 variant in BRCA1 has been reported in >100 individuals with breast and/or ovarian cancer (George 2013, Ghiorzo 2012, Meindl 2002, Pohlreich 2005, Sun 2017, Susswein 2015, Zhang 2011, Breast Cancer Information Core (BIC) ). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar VCV000017673.2). This variant has been identified in 0.004% (5/113572) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1253 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovarian cancer syndrome. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Ser1253Argfs*10) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357868, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 7894491, 21324516, 21989927, 23633455). This variant is also known as 3875del4. ClinVar contains an entry for this variant (Variation ID: 17673). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented “with untested allele” (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | May 19, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 17, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 06, 2023 | This variant deletes 4 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3875_3878delGTCT, 3875del4, 3875delGTCT in the literature based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast and ovarian cancer (PMID: 16168118, 21324516, 21989927, 22711857, 23633455) and pancreatic cancer (PMID: 21989927), and has been described as a common cause of hereditary breast-ovarian cancer in the French-Canadian population (PMID: 23199084). A breast cancer case-control meta-analysis reported this variant in 15/60466 cases and 2/53461 unaffected individuals with OR=6.633 (95%CI 1.517 to 29.005) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000278). This variant has been identified in 6/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2022 | The c.3756_3759delGTCT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 3756 to 3759, causing a translational frameshift with a predicted alternate stop codon (p.S1253Rfs*10). This recurrent mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families globally (Castilla LH et al. Nat. Genet. 1994 Dec;8:387-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Tedaldi G et al. Oncotarget. 2017 Jul;8:47064-47075; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3; Bhaskaran SP et al. Int. J. Cancer. 2019 Jan;[Epub ahead of print]). Of note, this alteration is also designated as 3875del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 18, 2021 | - - |
Familial cancer of breast Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change deletes 4 nucleotide from exon 11 of the BRCA1 mRNA (c.3756_3759delGTCT), causing a frameshift after codon 1253 and the creation of a premature translation stop signal 10 amino acid residues later- p.(Ser1253Argfs*10). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This variant has been reported in the literature in individuals with inherited breast and/or ovarian cancer, and prostate cancer (PMID: 7894491, 21324516). This variant is also as 3875del4 in the literature.This mutation has been described in the mutation database ClinVar (Variation ID:17673). - |
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Ser1253ArgfsX10 variant has been identified in 17 out of 6280 proband chromosomes (frequency 0.003) in individuals with breast and ovarian cancer phenotype, but not found in 200 control chromosomes included in these studies (Turner 1999, Langston 1996, Castilla 1994, Zhang 2011, Gaj 2012). It is also listed in dbSNP database presented ?with untested allele? (ID#: rs80357868) while no frequency information is provided; however, this variant has been listed 27X in the UMD and 123X in the BIC database as a clinically significant mutation. The p.Ser1253ArgfsX10 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1253 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to lead to a truncated or absent BRCA1 protein. Loss of function of the BRCA1 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic. - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
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