rs137852249
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000133.4(F9):c.881G>A(p.Arg294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,094,036 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294L) has been classified as Pathogenic.
Frequency
Consequence
NM_000133.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F9 | NM_000133.4 | c.881G>A | p.Arg294Gln | missense_variant | 8/8 | ENST00000218099.7 | |
F9 | NM_001313913.2 | c.767G>A | p.Arg256Gln | missense_variant | 7/7 | ||
F9 | XM_005262397.5 | c.752G>A | p.Arg251Gln | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F9 | ENST00000218099.7 | c.881G>A | p.Arg294Gln | missense_variant | 8/8 | 1 | NM_000133.4 | P1 | |
F9 | ENST00000394090.2 | c.767G>A | p.Arg256Gln | missense_variant | 7/7 | 1 | |||
F9 | ENST00000643157.1 | n.1548G>A | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 0.00000183 AC: 2AN: 1094036Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 359734
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Hereditary factor IX deficiency disease Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.58; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010602 / PMID: 2472424). A different missense change at the same codon (p.Arg294Gly) has been reported to be associated with F9 related disorder (PMID: 7937052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1992 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 15, 2023 | Variant summary: F9 c.881G>A (p.Arg294Gln) results in a conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179083 control chromosomes (gnomAD). c.881G>A has been reported in the literature in multiple individuals affected with Factor IX Deficiency (Hemophilia B) (Chen_1989, Chavali_2009, Onay_2003), including de novo occurrences. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.R294Q in F9 (NM_000133.4 has been reported previously in affected patients with hemophilia B (Chavali et al, 2009; Yu et al, 2012). The p.R294Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Experimental studies have shown that this missense change impairs intracellular trafficking of factor IX (Pignani et al, 2018). It has been submitted to ClinVar as Pathogenic. For these reasons, this variant has been classified as Pathogenic - |
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Jun 01, 2019 | - - |
Hereditary factor IX deficiency disease;C2749016:Thrombophilia, X-linked, due to factor 9 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 294 of the F9 protein (p.Arg294Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hemophilia B (PMID: 2472424, 19699296, 22544209, 32155688; Invitae). This variant is also known as p.Arg248Gln. ClinVar contains an entry for this variant (Variation ID: 10602). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on F9 protein function. Experimental studies have shown that this missense change affects F9 function (PMID: 29993188). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at