X-139561805-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000133.4(F9):c.1120G>A(p.Val374Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,210,191 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )
Consequence
F9
NM_000133.4 missense
NM_000133.4 missense
Scores
3
8
6
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 3.67
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain Peptidase S1 (size 232) in uniprot entity FA9_HUMAN there are 51 pathogenic changes around while only 0 benign (100%) in NM_000133.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.1120G>A | p.Val374Ile | missense_variant | 8/8 | ENST00000218099.7 | NP_000124.1 | |
F9 | NM_001313913.2 | c.1006G>A | p.Val336Ile | missense_variant | 7/7 | NP_001300842.1 | ||
F9 | XM_005262397.5 | c.991G>A | p.Val331Ile | missense_variant | 7/7 | XP_005262454.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.1120G>A | p.Val374Ile | missense_variant | 8/8 | 1 | NM_000133.4 | ENSP00000218099.2 | ||
F9 | ENST00000394090.2 | c.1006G>A | p.Val336Ile | missense_variant | 7/7 | 1 | ENSP00000377650.2 | |||
F9 | ENST00000643157.1 | n.1723+64G>A | intron_variant |
Frequencies
GnomAD3 genomes AF: 0.00000893 AC: 1AN: 111961Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34157
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GnomAD4 exome AF: 0.00000182 AC: 2AN: 1098230Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363590
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GnomAD4 genome AF: 0.00000893 AC: 1AN: 111961Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34157
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;T
Polyphen
B;.
Vest4
MutPred
Loss of catalytic residue at V374 (P = 0.1183);.;
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at