rs137852384
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM1PP3_StrongPP5_Very_StrongBS2
The NM_000132.4(F8):c.323A>C(p.Lys108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,637 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)
Consequence
F8
NM_000132.4 missense
NM_000132.4 missense
Scores
9
6
2
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 Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000132.4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
?
Variant X-154997038-T-G is Pathogenic according to our data. Variant chrX-154997038-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 10167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154997038-T-G is described in Lovd as [Likely_pathogenic].
BS2
?
High Hemizygotes in GnomAd at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
F8 | NM_000132.4 | c.323A>C | p.Lys108Thr | missense_variant | 3/26 | ENST00000360256.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.323A>C | p.Lys108Thr | missense_variant | 3/26 | 1 | NM_000132.4 | P1 | |
F8 | ENST00000423959.5 | c.218A>C | p.Lys73Thr | missense_variant | 3/6 | 3 | |||
F8 | ENST00000453950.1 | c.305A>C | p.Lys102Thr | missense_variant | 4/5 | 3 | |||
F8 | ENST00000647125.1 | c.*109A>C | 3_prime_UTR_variant, NMD_transcript_variant | 3/14 |
Frequencies
GnomAD3 genomes ? AF: 0.0000179 AC: 2AN: 111637Hom.: 0 Cov.: 23 AF XY: 0.0000592 AC XY: 2AN XY: 33811
GnomAD3 genomes
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GnomAD4 exome Cov.: 30
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GnomAD4 genome ? AF: 0.0000179 AC: 2AN: 111637Hom.: 0 Cov.: 23 AF XY: 0.0000592 AC XY: 2AN XY: 33811
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 06, 2017 | - - |
Hereditary factor VIII deficiency disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 1991 | - - |
Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;.;.
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at