chrX-154930152-AT-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS2PVS1PM2_SupportingPS4

This summary comes from the ClinGen Evidence Repository: The F8 c.3637del (p.Ile1213Phefs*5) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3. This variant has been reported in >16 probands with moderate to severe hemophilia, meeting phenotypic criteria for F8 (PMID:15921397; PMID:20533009; PMID:8307558; PMID:16601827). This variant has been reported both with and without the development of inhibitors. This variant is reported as de novo in at least seven probands with maternity confirmed in the affected male (PMID:29381227). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS2_Very Strong, PS4_Very Strong, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA255146/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

F8
NM_000132.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: -0.516

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.3637delA	p.Ile1213PhefsTer5	frameshift_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.3637delA	p.Ile1213PhefsTer5	frameshift_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*3303delA		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125 link	n.*3279delA		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

110571

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33045

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000963

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1089813

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357215

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000717

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000904

AC:

AN:

110571

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33045

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000963

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:7

Jun 01, 2019

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2024

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.3637delA (p.Ile1213PhefsX5) 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 variant allele was found at a frequency of 5.8e-06 in 1200384 control chromosomes. c.3637delA has been reported in the literature in multiple hemizygous male individuals affected with Factor VIII Deficiency (Hemophilia A), including several de novo cases (e.g. Lu_2018). These data indicate that the variant is very 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: 10253). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 25, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.3637delA; p.Ile1213PhefsTer5 variant (rs387906450) is reported in the literature in numerous individuals affected with hemophilia A, including multiple probands in which it was reported to occur de novo (Lu 2018, Factor VIII database and references therein). This variant is absent from general population databases (Exome Variant Server, 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 database: https://f8-db.eahad.org/ Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. -

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift deletion p.I1213Ffs*5 in F8 (NM_000132.4) has been reported previously in multiple patients with severe and moderate hemophilia A (Downes K et al,Albánez S et al). It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. It is novel (not in any individuals) in gnomAD ExomesThe p.I1213Ffs*5 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 described to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 25, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The F8 c.3637del (p.Ile1213Phefs*5) variant is a frameshift variant that is predicted to introduce a premature stop codon in exon 14 and expected to result in nonsense-mediated mRNA decay. This variant is completely absent from males in gnomAD v2.1.1 and gnomAD v3. This variant has been reported in >16 probands with moderate to severe hemophilia, meeting phenotypic criteria for F8 (PMID: 15921397; PMID: 20533009; PMID: 8307558; PMID: 16601827). This variant has been reported both with and without the development of inhibitors. This variant is reported as de novo in at least seven probands with maternity confirmed in the affected male (PMID: 29381227). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PVS1, PS2_Very Strong, PS4_Very Strong, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023) -

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Hemizygote Frameshift variant c.3637delA in Exon 14 of the F8 gene that results in the amino acid substitution p.Ile1213fs*5 was identified. The observed variant is noevel ingnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome VariantEnsemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMMv2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variantcan range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID:10253).This variant has been observed in many individuals affected with Hemophilia A reported by (Downes K et al., 2019). Based on the above evidence this variant has beenclassified as Pathogenic according to the ACMG guidelines. -

Hereditary factor IX deficiency disease

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:1

Mar 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in unrelated patients with Hemophilia A in published literature (PMID: 29381227); 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); This variant is associated with the following publications: (PMID: 34708896, 35014236, 31064749, 20331753, 33245802, 32897612, 33706050, 8307558, 29381227) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over