NM_000132.4(F8):c.4379del (p.Asn1460fs) AND Hereditary factor VIII deficiency disease

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Dec 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000010974.28

Allele description [Variation Report for NM_000132.4(F8):c.4379del (p.Asn1460fs)]

NM_000132.4(F8):c.4379del (p.Asn1460fs)

Gene:

F8:coagulation factor VIII [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000132.4(F8):c.4379del (p.Asn1460fs)

Other names:

F8, 1-BP DEL, FS

HGVS:

NC_000023.10:g.154157693delT
NC_000023.11:g.154929418del
NG_011403.2:g.98313del
NM_000132.4:c.4379delMANE SELECT
NP_000123.1:p.Asn1460fs
LRG_555t1:c.4379del
LRG_555:g.98313del
LRG_555p1:p.Asn1460fs
NC_000023.10:g.154157686delT
NC_000023.10:g.154157693del
NC_000023.10:g.154157693delT
NG_011403.1:g.98313del
NM_000132.3:c.4379delA
NM_000132.4:c.4379delAMANE SELECT
p.Asn1460fs

Protein change:

N1460fs

Links:

OMIM: 300841.0178; dbSNP: rs387906455

NCBI 1000 Genomes Browser:

rs387906455

Molecular consequence:

NM_000132.4:c.4379del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hereditary factor VIII deficiency disease (HEMA)
Synonyms:: AUTOSOMAL HEMOPHILIA A; Hemophilia A; Hemophilia A, congenital; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010602; MedGen: C0019069; Orphanet: 98878; OMIM: 306700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031201	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1993)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 1924291, 8281136
SCV000885393	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Oct 2, 2021)	germline	clinical testing	Citation Link,
SCV001142125	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002573789	Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV003841678	3billion, Medical Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1923751, 25741868
SCV004809647	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005884524	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 24, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis.

Higuchi M, Antonarakis SE, Kasch L, Oldenburg J, Economou-Petersen E, Olek K, Arai M, Inaba H, Kazazian HH Jr.

Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8307-11.

PubMed [citation]

PMID:: 1924291
PMCID:: PMC52497

Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.

Naylor J, Brinke A, Hassock S, Green PM, Giannelli F.

Hum Mol Genet. 1993 Nov;2(11):1773-8.

PubMed [citation]

PMID:: 8281136

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000031201.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 patients with severe hemophilia A (306700), Higuchi et al. (1991) and Naylor et al. (1993) identified the deletion of 1 nucleotide (A) resulting in a frameshift downstream from codons 1439, 1440 or 1441 in exon 14.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885393.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The F8 c.4379delA; p.Asn1460IlefsTer5 variant (rs387906455) also reported as c.4550delA; p.Asn1441IlefsTer5, is reported in multiple patients with severe hemophilia A (Naylor 1993, Tuddenham 1991, Wang 2010, Factor VIII variant database). This variant is also reported in ClinVar (Variation ID: 10261). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Factor VIII variant database: http://www.factorviii-db.org/ Naylor J et al. Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Hum Mol Genet. 1993; 2(11):1773-8. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucleic Acids Res. 1991; 19(18):4821-33. Wang X et al. The prevalence of factor VIII inhibitors and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia. 2010; 16(4):632-9.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001142125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe, SCV002573789.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, Medical Genetics, SCV003841678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010261 / PMID: 1923751). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004809647.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005884524.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: F8 c.4379delA (p.Asn1460IlefsX5) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4379delA has been reported in the literature in individuals affected with Hemophilia (example, Miller_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22103590). ClinVar contains an entry for this variant (Variation ID: 10261). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 13, 2025

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