chrX-154904999-G-C
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000132.4(F8):c.5398C>G(p.Arg1800Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 109,451 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R1800H) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.0000091 ( 0 hom., 1 hem., cov: 22)
Consequence
F8
NM_000132.4 missense
NM_000132.4 missense
Scores
10
6
Clinical Significance
Conservation
PhyloP100: 2.69
Publications
7 publications found
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]
F8 Gene-Disease associations (from GenCC):
- hemophilia AInheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
- mild hemophilia AInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- moderately severe hemophilia AInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- severe hemophilia AInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- symptomatic form of hemophilia A in female carriersInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 13 ACMG points.
PM1
In a hotspot region, there are 7 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-154904998-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10274.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant X-154904999-G-C is Pathogenic according to our data. Variant chrX-154904999-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10276.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.
Frequencies
GnomAD3 genomes 0.00000914 AC: 1AN: 109451Hom.: 0 Cov.: 22 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
109451
Hom.:
Cov.:
22
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome 0.00000914 AC: 1AN: 109451Hom.: 0 Cov.: 22 AF XY: 0.0000314 AC XY: 1AN XY: 31891 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
109451
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
31891
show subpopulations
African (AFR)
AF:
AC:
0
AN:
30034
American (AMR)
AF:
AC:
0
AN:
10265
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
2609
East Asian (EAS)
AF:
AC:
0
AN:
3523
South Asian (SAS)
AF:
AC:
0
AN:
2536
European-Finnish (FIN)
AF:
AC:
0
AN:
5609
Middle Eastern (MID)
AF:
AC:
0
AN:
237
European-Non Finnish (NFE)
AF:
AC:
1
AN:
52480
Other (OTH)
AF:
AC:
0
AN:
1476
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
2
-
-
Hereditary factor VIII deficiency disease (2)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at S1803 (P = 0.0744)
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
Publications
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