rs111033614

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PM1PM5PP2PP3_ModeratePP5_Very_StrongBS2_Supporting

The NM_000132.4(F8):c.5123G>A(p.Arg1708His) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,208,069 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1708C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 3 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.19

Publications

3 publications found

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]

F8 Gene-Disease associations (from GenCC):

hemophilia A
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
mild hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
moderately severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
severe hemophilia A
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of hemophilia A in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000132.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154928668-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.851

PP5

Variant X-154928667-C-T is Pathogenic according to our data. Variant chrX-154928667-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.5123G>A	p.Arg1708His	missense_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 link	c.5123G>A	p.Arg1708His	missense_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4		P00451-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

180265

AF XY:

0.0000154

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1096295

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

361855

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26298

American (AMR)

AF:

0.00

AC:

AN:

34925

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19281

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.0000373

AC:

AN:

53649

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

841357

Other (OTH)

AF:

0.00

AC:

AN:

46020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33964

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30744

American (AMR)

AF:

0.00

AC:

AN:

10557

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6059

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53111

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F8 c.5123G>A; p.Arg1708His variant (rs111033614), also known as p.Arg1689His, is reported in the literature in multiple individuals affected with mild hemophilia A (Gebhart 2018, Schwaab 1995, Factor VIII variant database and references therein), including at least one individual in which it arose de novo (Williams 2012). F8 activity in hemizygous individuals with this variant have been measured between 7%-43% of normal (Factor VIII variant database and references therein). This variant is found on only two chromosomes in the Genome Aggregation Database (2/180265 alleles), indicating it is not a common polymorphism. The arginine at codon 1708 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.885). Additionally, other amino acid substitutions at this codon (p.Arg1708Ser, p.Arg1708Cys, p.Arg1708Leu) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII variant database and references therein). Based on available information, the p.Arg1708His variant is considered to be pathogenic. References: Factor VIII variant database: https://f8-db.eahad.org/ Gebhart J et al. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). Haemophilia. 2018 May;24(3):405-413. PMID: 29388750. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64. PMID: 8547094. Williams VK et al. Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome. Int J Lab Hematol. 2012 Feb;34(1):98-101. PMID: 21707934. -

Jan 18, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23711294, 23020595, 19719828, 11179760, 24452774, 26628308, 20331761, 1851341, 8485051, 27734074, 29388750, 1064749, 21707934, 31064749, 36007526, 19473423, 32166871) -

Hereditary factor VIII deficiency disease

Pathogenic:2

Mar 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 20, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

F8-related disorder

Pathogenic:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The F8 c.5123G>A variant is predicted to result in the amino acid substitution p.Arg1708His. This variant (aka p.Arg1689His) has been reported in multiple individuals with mild hemophilia A or other bleeding disorders (Schwaab et al. 1991. PubMed ID: 1851341; Downes et al. 2019. PubMed ID: 31064749. Suppl3_SNV+INDEL; F8 database: https://www.factorviii-db.org/index.php). Different missense substitution at this same codon (p.Arg1708Cys; p.Arg1708Ser) have also been reported in patients with hemophilia A (Rydz et al. 2013. PubMed ID: 23913812; Lu et al. 2018. PubMed ID: 29381227) suggesting that amino acid residue p.Arg1708 is important for proper F8 protein function. This variant is reported in 0.0055% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Abnormality of coagulation

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PhyloP100

4.2

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.31

MutPred

0.80

Loss of MoRF binding (P = 0.0308);

MVP

0.99

MPC

0.35

ClinPred

0.94

GERP RS

5.0

Varity_R

0.66

gMVP

0.86

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over