rs137852382
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate
The NM_000132.4(F8):c.296T>C(p.Val99Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V99D) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 22)
Consequence
F8
NM_000132.4 missense
NM_000132.4 missense
Scores
4
8
5
Clinical Significance
Conservation
PhyloP100: 3.00
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain 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-154997065-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10165.Status of the report is no_assertion_criteria_provided, 0 stars.
PP5
?
Variant X-154997065-A-G is Pathogenic according to our data. Variant chrX-154997065-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 993612.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.296T>C | p.Val99Ala | missense_variant | 3/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.296T>C | p.Val99Ala | missense_variant | 3/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000423959.5 | c.191T>C | p.Val64Ala | missense_variant | 3/6 | 3 | |||
F8 | ENST00000453950.1 | c.278T>C | p.Val93Ala | missense_variant | 4/5 | 3 | |||
F8 | ENST00000647125.1 | c.*82T>C | 3_prime_UTR_variant, NMD_transcript_variant | 3/14 |
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
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 06, 2019 | The F8 c.296T>C; p.Val99Ala variant (rs137852382) is reported in the literature in multiple individuals affected with mild to moderate hemophilia A, including those with F8 activity measured between 5% and 14% of normal (Miller 2012, 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. The valine at codon 99 is highly conserved, and other amino acid substitutions at this codon (p.Val99Asp, p.Val99Phe) have been reported in individuals with hemophilia A and are considered disease-causing (Ravanbod 2012, Factor VIII database and references therein). Based on available information, the p.Val99Ala variant is considered to be pathogenic. References: Factor VIII database: http://f8-db.eahad.org Miller CH et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375-82. Ravanbod S et al. Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with haemophilia A. Haemophilia. 2012 May;18(3):e340-6. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Benign
D;T;T
Sift4G
Uncertain
D;.;.
Polyphen
D;D;.
Vest4
MutPred
Loss of stability (P = 0.0429);.;.;
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