rs137852388
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_000132.4(F8):c.396A>C(p.Glu132Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,206,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 113 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.396A>C | p.Glu132Asp | missense_variant | 4/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.396A>C | p.Glu132Asp | missense_variant | 4/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000423959.5 | c.291A>C | p.Glu97Asp | missense_variant | 4/6 | 3 | |||
F8 | ENST00000453950.1 | c.378A>C | p.Glu126Asp | missense_variant | 5/5 | 3 | |||
F8 | ENST00000647125.1 | c.*182A>C | 3_prime_UTR_variant, NMD_transcript_variant | 4/14 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 23AN: 112782Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5AN XY: 34914
GnomAD3 exomes AF: 0.000176 AC: 32AN: 182311Hom.: 1 AF XY: 0.000179 AC XY: 12AN XY: 66937
GnomAD4 exome AF: 0.000286 AC: 313AN: 1093906Hom.: 0 Cov.: 29 AF XY: 0.000301 AC XY: 108AN XY: 359350
GnomAD4 genome ? AF: 0.000204 AC: 23AN: 112836Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5AN XY: 34978
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 31, 2020 | The F8:c.396A>C variant is predicted to result in a missense change from glutamic acid to aspartic acid at amino acid 132 (p.Glu132Asp, formerly known as p.Glu113Asp). This variant has an allele frequency of 0.0003158 in non-Finnish European controls (gnomAD 2.1.2). This is significantly higher than expected for a pathogenic variant, given the incidence of haemophilia A (1/4000 males, PMID 32497379), and the proportion of symptomatic haemophilia A attributable to missense variation (17% severe and 81% non-severe haemophilia A, PMID 35770352) (BS1). This variant has been seen in cis to p.Arg612Cys (formerly p.Arg593Cys) in 22 Slovenian patients with Haemophilia A. In this study, an affected patient was identified with the less common p.Arg612Cys alone, but no patients had only F8:c.396A>C. This variant was also reported in cis to a frameshift variant in severe HA (PMID 11442643) (BP2). F8:c.396A>C has been reported in five patients with haemophilia A, prior to the availability of allele frequency databases (PMID 7984443, 19473423, 17445092, 15921397, 16173970), with 5 further unpublished cases on the EAHAD database. However, studies after the development of ACMG variant classification consider this variant benign or of unknown significance (eg. PMID 36007526, 34272389). In a multicentre analysis of US haemophilia treatment centres, with 8976 haemophilia A cases and 2358 haemophilia B cases, this variant was detected in haemophilia B patients and regarded as non-reportable (PMID 35770352). Locally, this variant was identified in two hemizygous males with no clinical or biochemical evidence of haemophilia A (BP5). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Jan 08, 2024 | - - |
F8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | The F8 c.396A>C variant is predicted to result in the amino acid substitution p.Glu132Asp. Using legacy nomenclature, this variant is also referred to as p.Glu113Asp). This variant has been reported to be causative for Hemophilia A (Freson et al. 1998. PubMed ID: 9603440; Markoff et al. 2009. PubMed ID: 19473423; Trampuš Bakija et al. 2015. PubMed ID: 26057490; Supplemental Table 2, Baz et al. 2021. PubMed ID: 34272389). Of note, another variant impacting the same amino acid has also been reported in individuals with Hemophilia A [c.395A>C (p.Glu132Ala, aka p.Glu113Ala using legacy nomenclature), Repesse et al. 2007. PubMed ID: 17445092]. This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | F8: PM1, PM5 - |
Hemorrhage Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at