rs137852443

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000132.4(F8):​c.5398C>T​(p.Arg1800Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,092,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: 22)
Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

F8
NM_000132.4 missense

Scores

13
3
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.69
Variant links:
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant X-154904999-G-A is Pathogenic according to our data. Variant chrX-154904999-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10275.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-154904999-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
F8NM_000132.4 linkuse as main transcriptc.5398C>T p.Arg1800Cys missense_variant 16/26 ENST00000360256.9 NP_000123.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
F8ENST00000360256.9 linkuse as main transcriptc.5398C>T p.Arg1800Cys missense_variant 16/261 NM_000132.4 ENSP00000353393 P1P00451-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.00000550
AC:
1
AN:
181798
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
66840
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
9.16e-7
AC:
1
AN:
1092018
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
357708
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000120
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 providedliterature onlyOMIMJan 01, 1992- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.68
D
BayesDel_noAF
Pathogenic
0.75
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.95
D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.3
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.70
MutPred
0.91
Loss of disorder (P = 0.024);
MVP
1.0
MPC
0.36
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.85
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.30
Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852443; hg19: chrX-154133274; API