X-154863124-C-T

Position:

chrX-154863124-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS2_Supporting

The NM_000132.4(F8):c.6533G>A(p.Arg2178His) variant causes a missense change. The variant allele was found at a frequency of 0.0000109 in 1,097,292 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.92

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant X-154863124-C-T is Pathogenic according to our data. Variant chrX-154863124-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154863124-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154863124-C-T is described in Lovd as [Pathogenic].

BS2

High Hemizygotes in GnomAdExome4 at 4 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/exons	MANE	Protein	UniProt
F8	NM_000132.4 link	c.6533G>A	p.Arg2178His	missense_variant	23/26	ENST00000360256.9	NP_000123.1	P00451-1
F8	NM_019863.3 link	c.128G>A	p.Arg43His	missense_variant	2/5		NP_063916.1	P00451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.6533G>A	p.Arg2178His	missense_variant	23/26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000330287.10 link	c.128G>A	p.Arg43His	missense_variant	2/5	1		ENSP00000327895.6	P00451-2
F8	ENST00000644698.1 link	c.266G>A	p.Arg89His	missense_variant	3/6			ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183351

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67835

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097292

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2024	Variant summary: F8 c.6533G>A (p.Arg2178His) results in a non-conservative amino acid change located in the Coagulation factor 5/8, C-terminal domain (IPR000421) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183351 control chromosomes. c.6533G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (Examples: Green_2008 and Miller_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18691168, 22103590). ClinVar contains an entry for this variant (Variation ID: 10319). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -

Hereditary factor IX deficiency disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 09, 2023

The F8 c.6533G>A; p.Arg2178His variant (rs137852465) is reported in the literature in multiple individuals affected with mild hemophilia A (see link to FVIII database and references therein). This variant is also reported in ClinVar (Variation ID: 10319). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.82). Additionally, other variants at this codon (c.6532C>T, p.Arg2178Cys; c.6533G>T, p.Arg2178Leu) have been reported in individuals with mild to moderate hemophilia A and are considered pathogenic (FVIII database). Based on available information, the p.Arg2178His variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/ -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Pathogenic

0.82

Sift

Benign

0.45

T;D;.

Sift4G

Benign

0.58

T;D;.

Polyphen

1.0

.;D;.

Vest4

0.54

MVP

0.99

MPC

2.1

ClinPred

0.99

GERP RS

5.7

Varity_R

0.75

gMVP

0.96

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.

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