rs137852404

Variant names:

• chrX-154969417-G-A
• rs137852404
• NM_000132.4:c.923C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4 PS2 PP3 PP1 PM2

This summary comes from the ClinGen Evidence Repository: The c.923C>T (NM_000132.3) variant in F8 is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 308 (p.Ser308Leu). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). This variant has been reported in at least 21 probands meeting the hemophilia A phenotype criteria specified by the Coagulation Factor Deficiency VCEP. Several probands are reported with mild hemophilia A (>4) and VWD 2N exclusion was reported in at least 2 probands (PS4_VeryStrong; PMID:10338101, 8759905, 19448530, 8449505, 18691168, 15921397, 19719828, 16972227, 18371166, 28674365, 30046696, 31026269, 21645180, 24845853, 22958177, 17445092). This variant has been identified as a de novo occurrence with confirmed maternal relationship (X-linked condition) in 1 male patient with severe hemophilia A (2 points per the ClinGen SVI PS2/PM6 table; PS2; PMID:1837116). The variant has been reported to segregate with mild hemophilia A in 2 affected siblings from 1 family (PP1; PMID:19448530). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.800, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has also been associated with discrepant factor VIII activity levels, with lower chromogenic factor VIII lab values (PMID:32232366). In summary, this variant meets the criteria to be classified as pathogenic for X-linked recessive hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4_VeryStrong, PS2, PP1, PP3, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0., Released 10/5/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA255082/MONDO:0010602/071

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.21
• Publications: 6 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.

• 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.
• PP3: 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.923C>T	p.Ser308Leu	missense	Exon 7 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.923C>T	p.Ser308Leu	missense	Exon 7 of 26	ENSP00000353393.4	P00451-1
	F8	ENST00000647125.1		n.*799C>T		non_coding_transcript_exon	Exon 8 of 14	ENSP00000496062.1	A0A2R8Y7J7
	F8	ENST00000647125.1		n.*799C>T		3_prime_UTR	Exon 8 of 14	ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097955 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363363

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841892

Other (OTH) AF: 0.00 AC: 0 AN: 46090

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary factor VIII deficiency disease (2)
1	-	-	F8-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.4	L
PhyloP100		7.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.80
Sift	Benign	0.65	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.81		Loss of glycosylation at S308 (P = 0.061)
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.99
Mutation Taster		=1/99	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: rs137852404; hg19: chrX-154197692; COSMIC: COSV64270281; COSMIC: COSV64270281;