rs111033613

Variant names:

• chrX-154928668-G-A
• rs111033613
• NM_000132.4:c.5122C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154928668-G-A
• chrX-154928668-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):​c.5122C>T​(p.Arg1708Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000896 in 111,629 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002048842: The arginine residue at this position is critical for the thrombin-mediated cleavage required to generate an activated F8 fragment (Pittman 1988), and p.Arg1708Cys variant prevents the processing of the F8 protein into the activated form (Arai 1990, Kamisue 1994).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1708H) has been classified as Likely pathogenic. The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.33
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• hemophilia A

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• mild hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• moderately severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe hemophilia A

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of hemophilia A in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for F8 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002048842: The arginine residue at this position is critical for the thrombin-mediated cleavage required to generate an activated F8 fragment (Pittman 1988), and p.Arg1708Cys variant prevents the processing of the F8 protein into the activated form (Arai 1990, Kamisue 1994).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-154928667-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to mild hemophilia A, hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-154928668-G-A is Pathogenic according to our data. Variant chrX-154928668-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.5122C>T	p.Arg1708Cys	missense	Exon 14 of 26	NP_000123.1	P00451-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.5122C>T	p.Arg1708Cys	missense	Exon 14 of 26	ENSP00000353393.4	P00451-1

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111629 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111629 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33819

African (AFR) AF: 0.00 AC: 0 AN: 30680

American (AMR) AF: 0.00 AC: 0 AN: 10551

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53103

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary factor VIII deficiency disease (4)
3	-	-	not provided (3)
1	-	-	FACTOR VIII (EAST HARTFORD) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.88		Gain of catalytic residue at P1707 (P = 0.0088)
MVP		0.99
MPC		0.36
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.92
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033613; hg19: chrX-154156943;