rs137852404

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3PP1PS4PS2

This summary comes from the ClinGen Evidence Repository: The c.923C>T (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 308 (p.Ser308Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant has been reported in at least 21 probands meeting the hemophilia A phenotype criteria specified by the Coagulation Factor Deficiency VCEP. Several probands are reported with mild hemophilia A (>4) and VWD 2N exclusion was reported in at least 2 probands (PS4_VeryStrong; PMID:10338101, 8759905, 19448530, 8449505, 18691168, 15921397, 19719828, 16972227, 18371166, 28674365, 30046696, 31026269, 21645180, 24845853, 22958177, 17445092). This variant has been identified as a de novo occurrence with confirmed maternal relationship (X-linked condition) in 1 male patient with severe hemophilia A (2 points per the ClinGen SVI PS2/PM6 table; PS2; PMID:1837116). The variant has been reported to segregate with mild hemophilia A in 2 affected siblings from 1 family (PP1; PMID:19448530). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has also been associated with discrepant factor VIII activity levels, with lower chromogenic factor VIII lab values (PMID:32232366). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PS2, PP1, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA255082/MONDO:0010602/071

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

F8
NM_000132.4 missense

Scores

8
5
4

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 7.21
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
F8NM_000132.4 linkc.923C>T p.Ser308Leu missense_variant Exon 7 of 26 ENST00000360256.9 NP_000123.1 P00451-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
F8ENST00000360256.9 linkc.923C>T p.Ser308Leu missense_variant Exon 7 of 26 1 NM_000132.4 ENSP00000353393.4 P00451-1
F8ENST00000647125.1 linkn.*799C>T non_coding_transcript_exon_variant Exon 8 of 14 ENSP00000496062.1 A0A2R8Y7J7
F8ENST00000647125.1 linkn.*799C>T 3_prime_UTR_variant Exon 8 of 14 ENSP00000496062.1 A0A2R8Y7J7

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097955
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
363363
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Bravo
AF:
0.0000227

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2
Pathogenic, reviewed by expert panelcurationClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, ClingenMay 09, 2024The c.923C>T (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 308 (p.Ser308Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant has been reported in at least 21 probands meeting the hemophilia A phenotype criteria specified by the Coagulation Factor Deficiency VCEP. Several probands are reported with mild hemophilia A (>4) and VWD 2N exclusion was reported in at least 2 probands (PS4_VeryStrong; PMID: 10338101, 8759905, 19448530, 8449505, 18691168, 15921397, 19719828, 16972227, 18371166, 28674365, 30046696, 31026269, 21645180, 24845853, 22958177, 17445092). This variant has been identified as a de novo occurrence with confirmed maternal relationship (X-linked condition) in 1 male patient with severe hemophilia A (2 points per the ClinGen SVI PS2/PM6 table; PS2; PMID: 1837116). The variant has been reported to segregate with mild hemophilia A in 2 affected siblings from 1 family (PP1; PMID: 19448530). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has also been associated with discrepant factor VIII activity levels, with lower chromogenic factor VIII lab values (PMID: 32232366). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PS2, PP1, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 1993- -
F8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 01, 2022The F8 c.923C>T variant is predicted to result in the amino acid substitution p.Ser308Leu. This variant is also described using legacy nomenclature as p.Ser289Leu, has been reported in multiple individuals with Hemophilia A (McGinniss et al. 1993. PubMed ID: 8449505; Bogdanova et al. 2007. PubMed ID: 16972227. Table S1; Castaman et al. 2009. PubMed ID: 19719828; Saito et al. 2017. PubMed ID: 28674365; F8 database: http://www.factorviii-db.org/advance_search.php). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 29, 2024The F8 c.923C>T, p.Ser308Leu variant (rs137852404), also known as Ser298Leu, is reported in multiple patients diagnosed with mild hemophilia A (Abu-Amero 2008, Bogdanova 2007, Castaman 2009, Fernandez-Lopez 2005, Represse 2007, Rudzki 1996, Strmecki 1999, Factor VIII variant database). Functional studies indicate that the variant is located near the heterotrimer contact surface (Markoff 2009), and increases the rate of dissociation after thrombin activation (Pipe 2001). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at residue 308 is highly conserved, and computational analyses predict that the variant is deleterious (REVEL: 0.80). Based on the above information, the variant is considered to be pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org/ Abu-Amero K et al. Spectrum of factor VIII mutations in Arab patients with severe haemophilia A. Haemophilia. 2008; 14(3):484-8. PMID: 18371166. Bogadnova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007; 28(1):54-60. PMID: 16972227. Castaman G et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. 2009; 7(11):1824-31. PMID: 19719828. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005; 90(5):707-10. PMID: 15921397. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009; 15(4):932-41. PMID: 19473423. Pipe S et al. Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa. Blood. 2001; 97(3):685-91. PMID: 11157485. Repesse Y et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost. 2007; 5(7):1469-76. PMID: 17445092. Rudzki Z et al. Mutations in a subgroup of patients with mild haemophilia A and a familial discrepancy between the one-stage and two-stage factor VIII:C methods. Br J Haematol. 1996; 94(2):400-6. PMID: 8759905. Strmecki L et al. Screen of 55 Slovenian haemophilia A patients: identification of 2 novel mutations (S-1R and IVS23+1G-->A) and discussion of mutation spectrum. Hum Mutat. 1999; 13(5):413. PMID: 10338101. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.86
D
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Benign
1.4
L
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-2.7
D
REVEL
Pathogenic
0.80
Sift
Benign
0.65
T
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.81
Loss of glycosylation at S308 (P = 0.061);
MVP
0.99
MPC
1.6
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.65
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs137852404; hg19: chrX-154197692; COSMIC: COSV64270281; COSMIC: COSV64270281; API