X-154861758-C-T

Variant names:

• chrX-154861758-C-T
• rs137852358
• NM_000132.4:c.6683G>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.6683G>A​(p.Arg2228Gln) 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. R2228P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.09

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 152) in uniprot entity FA8_HUMAN there are 31 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-154861758-C-T is Pathogenic according to our data. Variant chrX-154861758-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154861758-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.6683G>A	p.Arg2228Gln	missense_variant	Exon 24 of 26	ENST00000360256.9	NP_000123.1
F8	NM_019863.3	c.278G>A	p.Arg93Gln	missense_variant	Exon 3 of 5		NP_063916.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.6683G>A	p.Arg2228Gln	missense_variant	Exon 24 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000330287.10	c.278G>A	p.Arg93Gln	missense_variant	Exon 3 of 5	1		ENSP00000327895.6
F8	ENST00000644698.1	c.416G>A	p.Arg139Gln	missense_variant	Exon 4 of 6			ENSP00000495706.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000831

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Feb 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 01, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.6683G>A;p.Arg2228Gln variant (rs137852358), also known as Arg2209Gln, has been described in the literature in individuals with hemophilia with inconsistent severity classifications (see link and references therein). The variant is reported in ClinVar (Variation ID: 10098) but is absent from the Genome Aggregation Database, indicating is not a common polymorphism. The arginine at codon 2228 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.94). Taken together, this variant is considered pathogenic. References: Link to F8 database: http://www.factorviii-db.org/newstructure.php?aa_first=Arg&mut_id=1705&aa_last=Gln&variable=1705&hash=3361dcd5af0c49e04a7cc11718a9419c -

Hereditary factor IX deficiency disease Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.56
MutPred		0.92		.;Loss of MoRF binding (P = 0.0189);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.98

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: rs137852358; hg19: chrX-154090033;