rs137852435

Positions:

chrX-154931641-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The ENST00000360256.9(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 Conflicting classifications of pathogenicity (no stars). 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
ENST00000360256.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:1

Conservation

PhyloP100: 3.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a disulfide_bond (size 81) in uniprot entity FA8_HUMAN there are 126 pathogenic changes around while only 0 benign (100%) in ENST00000360256.9

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.

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10245.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=7, Uncertain_significance=1}. Variant chrX-154931641-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	14/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	14/26	1	NM_000132.4	ENSP00000353393	P1	P00451-1
F8	ENST00000647125.1 linkuse as main transcript	c.*1815C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14			ENSP00000496062

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

181533

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

67067

show subpopulations

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 SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000911

AC:

AN:

1097790

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	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

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	F8: PM1, PM2, PM5, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R698W); This variant is associated with the following publications: (PMID: 19473423, 8759905, 29388750, 23812942, 10404764, 15810915, 29296726, 31064749, 1301932, 18691168) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

Hereditary factor IX deficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Abnormality of coagulation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Thrombophilia, X-linked, due to factor 8 defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.92

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.92

Sift

Uncertain

0.018

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.86

Loss of methylation at R717 (P = 0.0253);

MVP

1.0

MPC

1.7

ClinPred

0.80

GERP RS

4.4

Varity_R

0.71

gMVP

0.99

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over