rs137852241
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000133.4(F9):c.677G>A(p.Arg226Gln) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R226W) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 22)
Consequence
F9
NM_000133.4 missense
NM_000133.4 missense
Scores
8
5
4
Clinical Significance
Conservation
PhyloP100: 5.36
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 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-139551217-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
?
Variant X-139551218-G-A is Pathogenic according to our data. Variant chrX-139551218-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10591.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.677G>A | p.Arg226Gln | missense_variant | 6/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.563G>A | p.Arg188Gln | missense_variant | 5/7 | ||
F9 | XM_005262397.5 | c.548G>A | p.Arg183Gln | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.677G>A | p.Arg226Gln | missense_variant | 6/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.563G>A | p.Arg188Gln | missense_variant | 5/7 | 1 | |||
F9 | ENST00000643157.1 | n.1344G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostics Department, Viafet Genomics Laboratory | Jan 11, 2016 | Viafet Genomics Laboratory has identified this variant in a female proband whose male offspring is presenting with Hemophilia B. This variant has been identified in several patients affected with Hemophilia B (PMIDs: 22639855 and 32875744). - |
Hemophilia b(m) Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1993 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Loss of catalytic residue at R226 (P = 0.0625);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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