X-154931641-G-A

Variant names:

• chrX-154931641-G-A
• rs137852435
• NM_000132.4:c.2149C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.2149C>T​(p.Arg717Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,097,790 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R717L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1
• Conservation: PhyloP100: 3.42

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]

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a disulfide_bond (size 81) in uniprot entity FA8_HUMAN there are 47 pathogenic changes around while only 0 benign (100%) in NM_000132.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154931640-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810977.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). GenCC associations: The gene is linked to hemophilia A, severe hemophilia A, moderately severe hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-154931641-G-A is Pathogenic according to our data. Variant chrX-154931641-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154931641-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.2149C>T	p.Arg717Trp	missense_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.2149C>T	p.Arg717Trp	missense_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*1815C>T		non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1
F8	ENST00000647125	n.*1791C>T		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181533 AF XY: 0.0000298

Gnomad AFR exome AF: 0.0000761

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: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097790 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 2 AN XY: 363236

Gnomad4 AFR exome AF: 0.0000379 AC: 1 AN: 26391

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35155

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19381

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30203

Gnomad4 SAS exome AF: 0.0000185 AC: 1 AN: 54127

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40499

Gnomad4 NFE exome AF: 0.00000713 AC: 6 AN: 841834

Gnomad4 Remaining exome AF: 0.0000434 AC: 2 AN: 46085

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:4 Uncertain:1

Dec 13, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: F8 c.2149C>T (p.Arg717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 181533 control chromosomes (gnomAD). c.2149C>T (also known as Arg698Trp) has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Gilmore_2010, Downes_2019). These data indicate that the variant is very likely to be associated with disease. In addition, other missense variants at the same codon, R717L and R717Q, has been classified as pathogenic in ClinVar, indicating the arginine residue is critical for F8 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 20148980, 31064749). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is associated with haemophilia A (MIM#306700), whereas gain of function due to copy number variations is associated with thrombophilia 13, X-linked, due to factor VIII defect (MIM#301071) (PMIDs: 23403259, 33275657). (I) 0108 - This gene is associated with both recessive and dominant disease. X-linked recessive inheritance is associated with haemophilia A (MIM#306700), whereas thrombophilia 13, X-linked, due to factor VIII defect (MIM#301071) has been reported with X-linked dominant inheritance (OMIM, PMID: 33275657). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygotes, 0 homozygotes, 2 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated plastocyanin-like 4 and F5/8 type A 2 domains (UniProt). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Arg717Gln) and p.(Arg717Leu) have been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). They have also been reported in multiple affected individuals (EAHAD F8 database). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in many individuals with mild haemophilia A (EAHAD F8 database, PMID: 18691168). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F8: PM1, PM2, PM5, PS4:Moderate -

Jun 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as p.(R698W); 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: 19473423, 8759905, 29388750, 23812942, 15810915, 29296726, 31064749, 10404764, 36007526, 1301932, 18691168) -

Apr 17, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.2149C>T; p.Arg717Trp variant (rs137852435), also known as Arg698Trp for legacy nomenclature, is reported in several patients diagnosed with mild hemophilia A (Diamond 1992, Gebhart 2018, Rudzki 1996, see Factor VIII variant database and references therein). This variant is reported in ClinVar (Variation ID: 10245) and is found in the general population with a low overall allele frequency of 0.001% (2/176848 alleles, including 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 717 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.916). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII variant database: http://www.factorviii-db.org/advance_search_results.php Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992; 1(3):248-57. PMID: 1301932. 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. 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. -

Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary factor IX deficiency disease Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Abnormality of coagulation Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.86		Loss of methylation at R717 (P = 0.0253);
MVP		1.0
MPC		1.7
ClinPred		0.80	D
GERP RS		4.4
Varity_R		0.71
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs137852435; hg19: chrX-154159916; COSMIC: COSV64271004;