rs137852471
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000132.4(F8):c.6865C>T(p.Gln2289Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (no stars).
Frequency
Genomes: not found (cov: 23)
Consequence
F8
NM_000132.4 stop_gained
NM_000132.4 stop_gained
Scores
2
1
2
Clinical Significance
Conservation
PhyloP100: 0.969
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 Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 35 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-154860467-G-A is Pathogenic according to our data. Variant chrX-154860467-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10330.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154860467-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.6865C>T | p.Gln2289Ter | stop_gained | 25/26 | ENST00000360256.9 | |
F8 | NM_019863.3 | c.460C>T | p.Gln154Ter | stop_gained | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.6865C>T | p.Gln2289Ter | stop_gained | 25/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000330287.10 | c.460C>T | p.Gln154Ter | stop_gained | 4/5 | 1 | |||
F8 | ENST00000644698.1 | c.598C>T | p.Gln200Ter | stop_gained | 5/6 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
D;D
Vest4
GERP RS
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