rs137852227
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000133.4(F9):c.223C>T(p.Arg75Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
F9
NM_000133.4 stop_gained
NM_000133.4 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 0.808
Genes affected
F9 (HGNC:3551): (coagulation factor IX) This gene encodes vitamin K-dependent coagulation factor IX that circulates in the blood as an inactive zymogen. This factor is converted to an active form by factor XIa, which excises the activation peptide and thus generates a heavy chain and a light chain held together by one or more disulfide bonds. The role of this activated factor IX in the blood coagulation cascade is to activate factor X to its active form through interactions with Ca+2 ions, membrane phospholipids, and factor VIII. Alterations of this gene, including point mutations, insertions and deletions, cause factor IX deficiency, which is a recessive X-linked disorder, also called hemophilia B or Christmas disease. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Sep 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-139537144-C-T is Pathogenic according to our data. Variant chrX-139537144-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10572.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.223C>T | p.Arg75Ter | stop_gained | 2/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.223C>T | p.Arg75Ter | stop_gained | 2/7 | ||
F9 | XM_005262397.5 | c.223C>T | p.Arg75Ter | stop_gained | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.223C>T | p.Arg75Ter | stop_gained | 2/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.223C>T | p.Arg75Ter | stop_gained | 2/7 | 1 | |||
F9 | ENST00000479617.2 | n.230C>T | non_coding_transcript_exon_variant | 2/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:3Other:1
Pathogenic, reviewed by expert panel | curation | ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Feb 09, 2024 | The F9 c.223C>T; p.Arg75Ter causes a protein truncation that is expected to undergo NMD, meeting PVS1. The variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting. Over 75 patients are reported in the literature with moderate-severe hemophilia B, some with a history of inhibitors to factor replacement products, meeting F9 phenotype criteria for PS4_Very strong and PP4_Moderate (EAHAD database; PMID: 29296726). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1, PS4_Very strong, PP4_Moderate, PM2_Supporting. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2023 | Variant summary: F9 c.223C>T (p.Arg75X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 182973 control chromosomes (gnomAD). c.223C>T has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (e.g. Li_2014). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24375831). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1990 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2022 | Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25929987, 18624698, 1969838, 25470321, 30648777, 32224444, 32155688, 23093250, 28193338, 24375831, 27824213, 32875744) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 18, 2020 | The F9 c.223C>T; p.Arg75Ter variant (rs137852227), also known as 6460G>A or Arg29Stop, is reported in the literature in individuals and families with hemophilia B, most often in cases of severe disease (Bottema 1993, Green 1989, Koeberl 1990, Factor IX database and references therein). Clotting assays of patient samples with this variant typically exhibit activity less than 1% of wildtype (Green 1989, Factor IX database). This variant is reported in ClinVar (Variation ID: 10572) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg75Ter variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Bottema CD et al. The pattern of spontaneous germ-line mutation: relative rates of mutation at or near CpG dinucleotides in the factor IX gene. Hum Genet. 1993 Jun;91(5):496-503. Green PM et al. Molecular pathology of haemophilia B. EMBO J. 1989 Apr;8(4):1067-72. Koeberl DD et al. Recurrent nonsense mutations at arginine residues cause severe hemophilia B in unrelated hemophiliacs. Hum Genet. 1990 Apr;84(5):387-90. - |
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2021 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in F9 are known to be pathogenic (PMID: 20301668). This variant has been reported in several individuals and families affected with hemophilia B (PMID: 1969838, 27824213, 25470321, 23093250, 18624698, 2198809). This variant is also known as 6460 C>T, Arg29-Stop, R248>TGA, and p.Arg29X in the literature. ClinVar contains an entry for this variant (Variation ID: 10572). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg75*) in the F9 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at