X-154863112-C-T

Position:

• chrX-154863112-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.6545G>A​(p.Arg2182His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2182C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.23

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154863113-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154863112-C-T is Pathogenic according to our data. Variant chrX-154863112-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154863112-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154863112-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6545G>A	p.Arg2182His	missense_variant	23/26	ENST00000360256.9
F8	NM_019863.3	c.140G>A	p.Arg47His	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6545G>A	p.Arg2182His	missense_variant	23/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.140G>A	p.Arg47His	missense_variant	2/5	1
F8	ENST00000644698.1	c.278G>A	p.Arg93His	missense_variant	3/6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 10, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2021	The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to Factor VIII database and references therein; Jayandharan 2017, Johnsen 2017, Tuddenham 1994). This variant is reported in ClinVar (Variation ID: 10320), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6544C>T; p.Arg2182Cys, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with severe hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res. 1994 Nov 11;22(22):4851-68. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2024	Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183342 control chromosomes. c.6545G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g.Miller_2012, Eckhardt_2013, Azadmehr_2021) . 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: 35014236, 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10320). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.88
MutPred		0.95		.;Loss of MoRF binding (P = 0.0613);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852466; hg19: chrX-154091387; COSMIC: COSV57704301;