NM_000132.4:c.43C>T

Variant names:

• chrX-155022510-G-A
• rs387906432
• NM_000132.4:c.43C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000132.4(F8):​c.43C>T​(p.Arg15*) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.456
• 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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 601 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-155022510-G-A is Pathogenic according to our data. Variant chrX-155022510-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.43C>T	p.Arg15*	stop_gained	Exon 1 of 26	NP_000123.1	P00451-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.43C>T	p.Arg15*	stop_gained	Exon 1 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000423959.5	TSL:3	c.38+4270C>T		intron	N/A	ENSP00000409446.1	B1B0G8
	F8	ENST00000453950.1	TSL:3	c.39-14C>T		intron	N/A	ENSP00000389153.1	B1B0G9

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary factor VIII deficiency disease (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.032	N
PhyloP100		0.46
Vest4		0.52
GERP RS		-1.4
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs387906432; hg19: chrX-154250785; COSMIC: COSV64270158; COSMIC: COSV64270158;