chrX-154930646-C-T

Variant names:

• chrX-154930646-C-T
• rs1060499784
• NM_000132.4:c.3144G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000132.4(F8):​c.3144G>A​(p.Trp1048*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.13
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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-154930646-C-T is Pathogenic according to our data. Variant chrX-154930646-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4	c.3144G>A	p.Trp1048*	stop_gained	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	c.3144G>A	p.Trp1048*	stop_gained	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4
F8	ENST00000647125.1	n.*2810G>A		non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1
F8	ENST00000647125.1	n.*2810G>A		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:1

Jan 27, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3144G>A (p.Trp1048*) nonsense variant in the F8 gene has not been previously reported; however, pathogenic variants occurring in the same codon and leading to the same nonsense change have previously been reported in individuals affected with severe Hemophilia A (Leuer et al., 2001; Hill et al., 2005). This c.3144G>A variant is predicted to cause a protein termination in exon 14 (out of a total of 26 exons in the coding sequence). Nonsense variants have been described in the F8 gene in several affected individuals (including nonsense variants downstream of this p.Trp1048* variant) and are, therefore, a common mechanism of disease. This c.3144G>A has not been reported in the population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). In silico algorithms predict this variant has a deleterious effect (GERP = 4.42; CADD = 40). Therefore, this collective evidence supports the classification of the c.3144G>A (p.Trp1048*) as an X-linked recessive Likely Pathogenic variant for Hemophilia A. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.12	N
PhyloP100		1.1
Vest4		0.92
GERP RS		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1060499784; hg19: chrX-154158921;