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.
ClinVar Genomic variation as it relates to human health
NM_000132.4(F8):c.4379del (p.Asn1460fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000132.4(F8):c.4379del (p.Asn1460fs)
Variation ID: 10261 Accession: VCV000010261.12
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: Xq28 X: 154929411 (GRCh38) [ NCBI UCSC ] X: 154157686 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 22, 2016 Apr 15, 2024 Apr 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000132.4:c.4379del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000123.1:p.Asn1460fs frameshift NM_000132.4:c.4379delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000132.3:c.4379delA NC_000023.11:g.154929418del NC_000023.10:g.154157693del NG_011403.2:g.98313del LRG_555:g.98313del LRG_555t1:c.4379del LRG_555p1:p.Asn1460fs - Protein change
- N1460fs
- Other names
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F8, 1-BP DEL, FS
- Canonical SPDI
- NC_000023.11:154929410:TTTTTTTT:TTTTTTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| F8 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
959 | 1235 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Apr 4, 2024 | RCV000010974.25 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001142125.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
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Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885393.2
First in ClinVar: Feb 18, 2019 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841678.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of the coagulation cascade (present) , Reduced factor VIII activity (present)
|
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Likely pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary factor VIII deficiency disease
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809647.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
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Pathogenic
(Nov 01, 1993)
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no assertion criteria provided
Method: literature only
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HEMOPHILIA A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031201.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
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 … (more)
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. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary factor VIII deficiency disease
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Pele Pequeno Principe Research Institute, Faculdades Pequeno Principe
Accession: SCV002573789.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Clinical Features:
Reduced factor VIII activity (present)
Sex: male
Geographic origin: Brazil
|
Comment:
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. | Naylor J | Human molecular genetics | 1993 | PMID: 8281136 |
| Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. | Higuchi M | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 1924291 |
| Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. | Tuddenham EG | Nucleic acids research | 1991 | PMID: 1923751 |
Text-mined citations for rs387906455 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.