chrX-154863151-C-T

Position:

• chrX-154863151-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000132.4(F8):​c.6506G>A​(p.Arg2169His) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,095,342 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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. R2169C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 3 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.54

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 14 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154863152-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2637834.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant X-154863151-C-T is Pathogenic according to our data. Variant chrX-154863151-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154863151-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154863151-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.6506G>A	p.Arg2169His	missense_variant	23/26	ENST00000360256.9
F8	NM_019863.3	c.101G>A	p.Arg34His	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.6506G>A	p.Arg2169His	missense_variant	23/26	1	NM_000132.4	P1
F8	ENST00000330287.10	c.101G>A	p.Arg34His	missense_variant	2/5	1
F8	ENST00000644698.1	c.239G>A	p.Arg80His	missense_variant	3/6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095342 Hom.: 0 Cov.: 30 AF XY: 0.00000832 AC XY: 3 AN XY: 360742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 13, 2023	The F8 c.6506G>A; p.Arg2169His variant (rs137852461), also known as Arg2150His, is reported in the literature in individuals with mild to moderate hemophilia A (see F8 database and references therein, Bogdanova 2007, Diamond 1992, Green 2008, Higuchi 1991, Suzuki 2018). This variant is reported in ClinVar (Variation ID: 10315) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2169 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: http://www.factorviii-db.org/ Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. 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. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. Suzuki et al. Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family. Haemophilia. 2018 Jan;24(1):e13-e16. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000; van den Biggelarr et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R2150H); This variant is associated with the following publications: (PMID: 19473423, 34708896, 35014236, 18691168, 32589464, 21883705, 16972227, 20800587, 19719828, 18387975, 1908096, 29082580, 30046696, 31064749, 18565236, 17610549, 17445092, 17222201, 16769589, 16173970, 12871415, 11857744, 11442643, 11341489, 10910910, 10896236, 10404764, 10338101, 1301932, 33245802, 33706050, 32897612, 15921397, 21909383) -

Hereditary factor VIII deficiency disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 14, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Jun 01, 2019	- -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;T;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.7	D;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.74
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.99

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

Other links and lift over

dbSNP: rs137852461; hg19: chrX-154091426;