rs137852467

chrX-154863113-G-A

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.6544C>T(p.Arg2182Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000179 in 111,962 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. R2182H) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.05

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 disulfide_bond (size 148) in uniprot entity FA8_HUMAN there are 71 pathogenic changes around while only 0 benign (100%) 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-154863113-G-A is Pathogenic according to our data. 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. Variant chrX-154863113-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154863113-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6544C>T	p.Arg2182Cys	missense_variant	23/26	ENST00000360256.9
F8	NM_019863.3	c.139C>T	p.Arg47Cys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6544C>T	p.Arg2182Cys	missense_variant	23/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.139C>T	p.Arg47Cys	missense_variant	2/5	1
F8	ENST00000644698.1	c.277C>T	p.Arg93Cys	missense_variant	3/6

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111962 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34118

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

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183342 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67830

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 Cov.: 30

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111962 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34118

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000132

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2020	The F8 c.6544C>T; p.Arg2182Cys variant (rs137852467), also known as p.Arg2163Cys, is reported in the literature in numerous individuals affected with moderate to severe Hemophilia A (see link to Factor VIII database, Citron 2002, Jayandharan 2009, Liu 2000, Lu 2018, Factor VIII variant database). This variant is reported in ClinVar (Variation ID: 10321) and is found in the general population with an overall allele frequency of 0.0006% (1/178610 alleles) in the Genome Aggregation Database. 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.6545G>A; p.Arg2182His, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with Hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009, Liu 2000, Factor VIII variant database). Based on available information, this variant is considered to be pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org Citron M et al. High throughput mutation screening of the factor VIII gene (F8C) in hemophilia A: 37 novel mutations and genotype-phenotype correlation. Hum Mutat. 2002 Oct;20(4):267-74. Factor VIII variant 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. Liu ML et al. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood. 2000 Aug 1;96(3):979-87. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1992	- -

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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.79
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.7	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		0.94		.;Gain of sheet (P = 0.0344);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
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

Other links and lift over

dbSNP: rs137852467; hg19: chrX-154091388; COSMIC: COSV57704780;