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):āc.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
Consequence
NM_000133.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.1328T>C | p.Ile443Thr | missense_variant | 8/8 | ENST00000218099.7 | NP_000124.1 | |
F9 | NM_001313913.2 | c.1214T>C | p.Ile405Thr | missense_variant | 7/7 | NP_001300842.1 | ||
F9 | XM_005262397.5 | c.1199T>C | p.Ile400Thr | missense_variant | 7/7 | XP_005262454.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.1328T>C | p.Ile443Thr | missense_variant | 8/8 | 1 | NM_000133.4 | ENSP00000218099.2 | ||
F9 | ENST00000394090.2 | c.1214T>C | p.Ile405Thr | missense_variant | 7/7 | 1 | ENSP00000377650.2 | |||
F9 | ENST00000643157.1 | n.1723+272T>C | intron_variant |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097643Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1AN XY: 363017
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2024 | Variant 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 provided | literature only | OMIM | Jun 01, 1991 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 17, 2021 | PP3, PP4, PP5, PM1, PM2, PS4_Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 24, 2019 | The 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 17, 2023 | Experimental 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at