chrX-139541078-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000133.4(F9):​c.280G>A​(p.Gly94Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

F9
NM_000133.4 missense, splice_region

Scores

10
3
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.17
Variant links:
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.

PM1
In a chain Coagulation factor IXa light chain (size 144) in uniprot entity FA9_HUMAN there are 37 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, 0.989
PP5
Variant X-139541078-G-A is Pathogenic according to our data. Variant chrX-139541078-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454496.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
F9NM_000133.4 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant, splice_region_variant 4/8 ENST00000218099.7 NP_000124.1 P00740-1
F9XM_005262397.5 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant, splice_region_variant 4/7 XP_005262454.1
F9NM_001313913.2 linkuse as main transcriptc.277+3692G>A intron_variant NP_001300842.1 P00740-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
F9ENST00000218099.7 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant, splice_region_variant 4/81 NM_000133.4 ENSP00000218099.2 P00740-1
F9ENST00000394090.2 linkuse as main transcriptc.277+3692G>A intron_variant 1 ENSP00000377650.2 P00740-2
F9ENST00000479617.2 linkuse as main transcriptn.242-9G>A intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1071072
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
341494
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 28, 2017In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in multiple individuals affected with mild hemophilia B (PMID: 20305539, 10595634, 1796396, 19699296). This variant is also known as 10394G>A and Gly48Arg in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 94 of the F9 protein (p.Gly94Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Pathogenic
0.64
D
BayesDel_noAF
Pathogenic
0.69
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.79
D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
0.41
N
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.83
Loss of catalytic residue at G94 (P = 0.0768);
MVP
1.0
MPC
3.3
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.94
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.20
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1556437035; hg19: chrX-138623237; API