X-139562013-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000133.4(F9):ā€‹c.1328T>Cā€‹(p.Ile443Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,643 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 22)
Exomes š‘“: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

F9
NM_000133.4 missense

Scores

8
8
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a chain Coagulation factor IXa heavy chain (size 234) 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, 0.988
PP5
Variant X-139562013-T-C is Pathogenic according to our data. Variant chrX-139562013-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
F9NM_000133.4 linkuse as main transcriptc.1328T>C p.Ile443Thr missense_variant 8/8 ENST00000218099.7 NP_000124.1 P00740-1
F9NM_001313913.2 linkuse as main transcriptc.1214T>C p.Ile405Thr missense_variant 7/7 NP_001300842.1 P00740-2
F9XM_005262397.5 linkuse as main transcriptc.1199T>C p.Ile400Thr missense_variant 7/7 XP_005262454.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
F9ENST00000218099.7 linkuse as main transcriptc.1328T>C p.Ile443Thr missense_variant 8/81 NM_000133.4 ENSP00000218099.2 P00740-1
F9ENST00000394090.2 linkuse as main transcriptc.1214T>C p.Ile405Thr missense_variant 7/71 ENSP00000377650.2 P00740-2
F9ENST00000643157.1 linkuse as main transcriptn.1723+272T>C intron_variant

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097643
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
1
AN XY:
363017
show subpopulations
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary factor IX deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 27, 2024Variant summary: F9 c.1328T>C (p.Ile443Thr) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR0012540) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182978 control chromosomes (gnomAD). c.1328T>C has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (example: 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). ClinVar contains an entry for this variant (Variation ID: 10627). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 1991- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 17, 2021PP3, PP4, PP5, PM1, PM2, PS4_Moderate -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 24, 2019The F9 c.1328T>C; p.Ile443Thr variant (rs137852268), also known as p.Ile397Thr or as the F9 Vancouver variant, is reported in the literature in numerous individuals and families affected with mild, moderate, or severe hemophilia B (Geddes 1989, Ketterling 1991, Li 2014, Thompson 1990, Factor IX database and references therein). This variant is one of the most common pathogenic variants in hemophilia B patients of European descent (Ketterling 1991), and individuals with this variant carry a shared haplotype, suggestive of a founder effect (Ketterling 1991, Thompson 1990). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Samples from affected individuals with this variant exhibit clotting activity at 12% or less of normal activity (Factor IX database and references therein). Additionally, enzymatic studies of p.Ile443Thr protein demonstrate substantially reduced catalytic efficiency (Geddes 1989). Based on available information, this variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Geddes VA et al. A moderate form of hemophilia B is caused by a novel mutation in the protease domain of factor IXVancouver. J Biol Chem. 1989 Mar 15;264(8):4689-97. Ketterling RP et al. Evidence that descendants of three founders constitute about 25% of hemophilia B in the United States. Genomics. 1991 Aug;10(4):1093-6. Li T et al. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014 Apr;89(4):375-9. Thompson AR et al. "Founder" effect in different families with haemophilia B mutation. Lancet. 1990 Feb 17;335(8686):418. -
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 17, 2023Experimental studies have shown that this missense change affects F9 function (PMID: 2494175). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 443 of the F9 protein (p.Ile443Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 2494175, 24375831). This variant is also known as p.Ile397Thr and "Factor IX Vancouver". ClinVar contains an entry for this variant (Variation ID: 10627). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt F9 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.2
M;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-4.1
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
0.97
D;.
Vest4
0.70
MutPred
0.95
Loss of stability (P = 0.0048);.;
MVP
1.0
MPC
1.8
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.91
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs137852268; hg19: chrX-138644172; API