X-154929410-AT-ATT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000132.4(F8):c.4379dupA(p.Asn1460LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

F8
NM_000132.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.866

Publications

5 publications found

Variant links:

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

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-154929410-A-AT is Pathogenic according to our data. Variant chrX-154929410-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1333164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.4379dupA	p.Asn1460LysfsTer2	frameshift_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 link	c.4379dupA	p.Asn1460LysfsTer2	frameshift_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000556

AC:

AN:

179894

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1096940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362568

African (AFR)

AF:

0.00

AC:

AN:

26348

American (AMR)

AF:

0.00

AC:

AN:

35150

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54055

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40457

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841198

Other (OTH)

AF:

0.00

AC:

AN:

46043

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:3

Aug 15, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 26, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: F8 c.4379dupA (p.Asn1460LysfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.4379dupA has been observed in individual(s) affected with Factor VIII Deficiency (Hemophilia A) (Lu_2018). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29381227). ClinVar contains an entry for this variant (Variation ID: 1333164). Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frameshift duplication p.N1460Kfs*2 in F8 (NM_000132.4) has been reported in multiple affected indviduals (AbdulGhafar A et al,Hwang SH et al). It has been submitted to ClinVar as PathogenicAlthough the variant is present at 0.0006% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.N1460Kfs*2 variant is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation.Loss of function variants have been reported previously as disease causing. For these reasons, this variant has been classified as Likely Pathogenic -

Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect

Pathogenic:2

Nov 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PS4_Supporting+PP4 -

not provided

Pathogenic:2

Nov 15, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also denoted as c.4372insA due to alternative nomenclature; This variant is associated with the following publications: (PMID: 1908096, 7794769, 11102988, 8054459, 10519986, 19473408, 19686262, 18388498, 35014236, 20838461, 12325022, 12871415, 9603440, 10896236, 11298607, 11843836, 11857744, 12195713, 16601827, 18403393, 19719548, 20028422, 20800587, 29381227, 18691168, 33245802, 32497951, 32897612) -

Jul 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F8 c.4379dupA; p.Asn1460LysfsTer2 variant (rs387906455), also known as p.Asn1442LysfsTer2, is reported in numerous individuals with hemophilia A (see Factor VIII database, Lu 2018). In vitro functional analyses demonstrate that individuals with this variant have factor VIII activity of <1-8%. It is reported in one allele in the Genome Aggregation Database, but is considered a low confidence variant in that database. This variant causes a frameshift by inserting 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: Link to Factor VIII database: https://f8-db.eahad.org/index.php Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. PMID: 29381227. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.87

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over