F8 p.Arg2169His

Variant names:

• chrX-154863151-C-T
• rs137852461
• NM_000132.4:c.6506G>A
• F8 p.Arg2169His

Your query was ambiguous. Multiple possible variants found:

• chrX-154863151-C-T
• chrX-154863150-AC-GT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM1 PM5 PP2 PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005201770: Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2169L) has been classified as Likely pathogenic. The gene F8 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 3 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 4.54
• Publications: 15 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: ClinGen, Labcorp Genetics (formerly Invitae)
• 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 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005201770: 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); 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
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000132.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154863151-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4081672.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, 0.922
• PP5: Variant X-154863151-C-T is Pathogenic according to our data. Variant chrX-154863151-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10315.

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.6506G>A	p.Arg2169His	missense	Exon 23 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.101G>A	p.Arg34His	missense	Exon 2 of 5	NP_063916.1	P00451-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.6506G>A	p.Arg2169His	missense	Exon 23 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.101G>A	p.Arg34His	missense	Exon 2 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.239G>A	p.Arg80His	missense	Exon 3 of 6	ENSP00000495706.1	A0A2R8Y707

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

African (AFR) AF: 0.00 AC: 0 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.00 AC: 0 AN: 54076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839484

Other (OTH) AF: 0.00 AC: 0 AN: 45998

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	-	Hereditary factor VIII deficiency disease (6)
4	-	-	not provided (4)
1	-	-	Hereditary factor IX deficiency disease (1)
1	-	-	Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.97
gMVP		0.99
Mutation Taster		=5/95	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs137852461;

hg19: chrX-154091426;