rs387906450
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS2PVS1PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The F8 c.3637del (p.Ile1213Phefs*5) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3. This variant has been reported in >16 probands with moderate to severe hemophilia, meeting phenotypic criteria for F8 (PMID:15921397; PMID:20533009; PMID:8307558; PMID:16601827). This variant has been reported both with and without the development of inhibitors. This variant is reported as de novo in at least seven probands with maternity confirmed in the affected male (PMID:29381227). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS2_Very Strong, PS4_Very Strong, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA255146/MONDO:0010602/071
Frequency
Consequence
NM_000132.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.3637del | p.Ile1213PhefsTer5 | frameshift_variant | 14/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.3637del | p.Ile1213PhefsTer5 | frameshift_variant | 14/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000647125.1 | c.*3303del | 3_prime_UTR_variant, NMD_transcript_variant | 14/14 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 110571Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33045 FAILED QC
GnomAD4 exome AF: 0.00000551 AC: 6AN: 1089813Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 357215
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000904 AC: 1AN: 110571Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33045
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1993 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Hemizygote Frameshift variant c.3637delA in Exon 14 of the F8 gene that results in the amino acid substitution p.Ile1213fs*5 was identified. The observed variant is noevel ingnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome VariantEnsemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMMv2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variantcan range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID:10253).This variant has been observed in many individuals affected with Hemophilia A reported by (Downes K et al., 2019). Based on the above evidence this variant has beenclassified as Pathogenic according to the ACMG guidelines. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 25, 2022 | The F8 c.3637delA; p.Ile1213PhefsTer5 variant (rs387906450) is reported in the literature in numerous individuals affected with hemophilia A, including multiple probands in which it was reported to occur de novo (Lu 2018, Factor VIII database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: https://f8-db.eahad.org/ Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. - |
Pathogenic, no assertion criteria provided | clinical testing | Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Jun 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The frameshift deletion p.I1213Ffs*5 in F8 (NM_000132.4) has been reported previously in multiple patients with severe and moderate hemophilia A (Downes K et al,Albánez S et al). It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. It is novel (not in any individuals) in gnomAD ExomesThe p.I1213Ffs*5 variant is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been described to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary factor IX deficiency disease Pathogenic:1
Likely 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