X-154929410-AT-ATT

Position:

• chrX-154929410-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000132.4(F8):​c.4379dupA​(p.Asn1460fs) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.866

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 1333164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.4379dupA	p.Asn1460fs	frameshift_variant	14/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.4379dupA	p.Asn1460fs	frameshift_variant	14/26	1	NM_000132.4	ENSP00000353393.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1096940 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362568

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4_Supporting+PP4 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2023	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) -

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 1991	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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 -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs387906455; hg19: chrX-154157685;