X-154966525-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000132.4(F8):c.1172G>A(p.Arg391His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R391C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 22)
Consequence
F8
NM_000132.4 missense
NM_000132.4 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 4.02
Genes affected
F8 (HGNC:3546): (coagulation factor VIII) This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
?
In a site Cleavage; by thrombin (size 1) in uniprot entity FA8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000132.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-154966526-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10125.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
?
Variant X-154966525-C-T is Pathogenic according to our data. Variant chrX-154966525-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154966525-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154966525-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.1172G>A | p.Arg391His | missense_variant | 8/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.1172G>A | p.Arg391His | missense_variant | 8/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000647125.1 | c.*1048G>A | 3_prime_UTR_variant, NMD_transcript_variant | 9/14 | |||||
F8 | ENST00000483822.2 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 16, 2019 | The F8 c.1172G>A; p.Arg391His variant (rs28935499), also known as p.Arg372His for legacy nomenclature, has been described in several individuals affected with hemophilia A (see link to factor VIII database and references therein). It is reported in Clinvar (Variation ID: 10111) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 391 is conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. In vitro functional studies of this variant protein demonstrate a significant reduction in thrombin-catalyzed activation and function (Nogami 2005). Additionally, other variants at this codon (p.Arg391Pro, p.Arg391Leu) have been observed in individuals affected with hemophilia A and are considered pathogenic (see link to factor VIII database and references therein). Based on available information, this variant is considered pathogenic. References: Link to Factor 8 database: http://www.factorviii-db.org/ Nogami K et al. Thrombin-catalyzed activation of factor VIII with His substituted for Arg372 at the P1 site. Blood. 2005;105(11):4362-8. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 05, 2019 | - - |
Hereditary factor IX deficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
FACTOR VIII (OKAYAMA) Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1989 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.028);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at