rs28933677

Variant names:

• chrX-154904839-G-A
• rs28933677
• NM_000132.4:c.5558C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154904839-G-A
• chrX-154904839-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000132.4(F8):​c.5558C>T​(p.Ala1853Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.67
• Publications: 2 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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 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
• 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 hemophilia A, mild 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, 0.977
• PP5: Variant X-154904839-G-A is Pathogenic according to our data. Variant chrX-154904839-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10284.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.5558C>T	p.Ala1853Val	missense_variant	Exon 16 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.5558C>T	p.Ala1853Val	missense_variant	Exon 16 of 26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

May 05, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000132.3(F8):c.5558C>T(A1853V) is a missense variant classified as likely pathogenic in the context of hemophilia A. A1853V has been observed in cases with relevant disease (PMID: 18387975, 32897612, 8307558). Relevant functional assessments of this variant are not available in the literature. A1853V has not been observed in referenced population frequency databases. In summary, NM_000132.3(F8):c.5558C>T(A1853V) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.80
Sift	Benign	0.10	T
Sift4G	Uncertain	0.019	D
Vest4		0.72
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.54
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28933677; hg19: chrX-154133114;