NM_000132.4:c.6976C>T

Variant names:

• chrX-154837677-G-A
• rs137852354
• NM_000132.4:c.6976C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4 PVS1_Moderate PS2_Moderate PP1 PP4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6976C>T (p.Arg2326Ter) creates a premature stop codon in exon 26, which is the last exon of the F8 gene. Therefore, protein is not expected to undergo NMD and meets PVS1_Strong. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. More than 20 patients are reported in the literature with severe/moderate hemophilia A, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate. The variant was also reported in two affected brothers and their carrier mother, which meets criteria for PP1 (PMID:2987704). There is also at least one report of a de novo case where maternity was not confirmed, meeting PS2_Moderate (PMID:2104741). 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 F9: PVS1_Strong, PS4_Very strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255007/MONDO:0010602/071

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: -0.209
• Publications: 5 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: 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.6976C>T	p.Arg2326*	stop_gained	Exon 26 of 26	NP_000123.1	P00451-1
	F8	NM_019863.3		c.571C>T	p.Arg191*	stop_gained	Exon 5 of 5	NP_063916.1	P00451-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.6976C>T	p.Arg2326*	stop_gained	Exon 26 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000330287.10	TSL:1	c.571C>T	p.Arg191*	stop_gained	Exon 5 of 5	ENSP00000327895.6	P00451-2
	F8	ENST00000644698.1		c.709C>T	p.Arg237*	stop_gained	Exon 6 of 6	ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Benign	0.96
FATHMM_MKL	Benign	0.018	N
PhyloP100		-0.21
Vest4		0.74
GERP RS		-3.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137852354; hg19: chrX-154065952; COSMIC: COSV57704724; COSMIC: COSV57704724;