chrX-139548455-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000133.4(F9):c.484C>T(p.Arg162Ter) 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
2
1
Clinical Significance
Conservation
PhyloP100: 3.54
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 19 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;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant X-139548455-C-T is Pathogenic according to our data. Variant chrX-139548455-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.484C>T | p.Arg162Ter | stop_gained | 5/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.370C>T | p.Arg124Ter | stop_gained | 4/7 | ||
F9 | XM_005262397.5 | c.392-2607C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.484C>T | p.Arg162Ter | stop_gained | 5/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.370C>T | p.Arg124Ter | stop_gained | 4/7 | 1 | |||
F9 | ENST00000643157.1 | n.1151C>T | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Jun 01, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1990 | - - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 11, 2018 | The F9 c.484C>T; p.Arg162Ter variant (rs137852272), also known as Arg116Ter, has been described in multiple individuals affected with severe hemophilia B (see link to F9 database and references therein, Lin 2018). It contains and entry in ClinVar (Variation ID: 10640) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and 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, this variant is considered pathogenic. REFERENCES Link to F9 database: http://www.factorix.org/ Lin X et al. Establishing a comprehensive genetic diagnosis strategy for hemophilia B and its application in Chinese population. Int J Lab Hematol. 2018 Apr;40(2):215-228. - |
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change creates a premature translational stop signal (p.Arg162*) in the F9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F9 are known to be pathogenic (PMID: 20301668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hemophilia B (PMID: 32875744). This variant is also known as 17,761C>T 116R>stop. ClinVar contains an entry for this variant (Variation ID: 10640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
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
DS_DL_spliceai
Position offset: 36
Find out detailed SpliceAI scores and Pangolin per-transcript scores at