rs28933670

Positions:

• chrX-154966483-A-C
• chrX-154966483-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP4_Moderate PM5_Supporting PM2_Supporting PP3 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The variant, NM_000132.3(F8):c.1214T>G causes a missense change, Ile405Ser, which is not reported in gnomAD v2.1.1 or v3 or v4. This variant has been reported in at least three patients with Hemophilia A in the literature (PS4_Moderate, PP4_Moderate, PMIDs: 8307558). The variant has a REVEL score of 0.985 (PP3 threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255098/MONDO:0010602/071

• Frequency: Genomes: not found (cov: 22)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.42

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 Likely_pathogenic. Variant got 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.1214T>G	p.Ile405Ser	missense_variant	8/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.1214T>G	p.Ile405Ser	missense_variant	8/26	1	NM_000132.4	P1
F8	ENST00000483822.2	n.34T>G		non_coding_transcript_exon_variant	1/2	3
F8	ENST00000647125.1	c.*1090T>G		3_prime_UTR_variant, NMD_transcript_variant	9/14

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	May 09, 2024	The variant, NM_000132.3(F8):c.1214T>G causes a missense change, Ile405Ser, which is not reported in gnomAD v2.1.1 or v3 or v4. This variant has been reported in at least three patients with Hemophilia A in the literature (PS4_Moderate, PP4_Moderate, PMIDs: 8307558). The variant has a REVEL score of 0.985 (PP3 threshold >0.6). Another variant at the same codon, Ile405Thr, is curated by the Coagulation Factor Deficiency Variant Curation Expert Panel as likely pathogenic (PM5_Supporting). In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Moderate, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	0.99	A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of disorder (P = 0.0214);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28933670; hg19: chrX-154194758;