X-154969417-G-A

Position:

• chrX-154969417-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3 PP1 PM2 PS4 PS2

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 ENST00000360256.9 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.21

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 Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4	c.923C>T	p.Ser308Leu	missense_variant	7/26	ENST00000360256.9	NP_000123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9	c.923C>T	p.Ser308Leu	missense_variant	7/26	1	NM_000132.4	ENSP00000353393	P1
F8	ENST00000647125.1	c.*799C>T		3_prime_UTR_variant, NMD_transcript_variant	8/14			ENSP00000496062

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1993	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	May 09, 2024	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). -

F8-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

The F8 c.923C>T variant is predicted to result in the amino acid substitution p.Ser308Leu. This variant is also described using legacy nomenclature as p.Ser289Leu, has been reported in multiple individuals with Hemophilia A (McGinniss et al. 1993. PubMed ID: 8449505; Bogdanova et al. 2007. PubMed ID: 16972227. Table S1; Castaman et al. 2009. PubMed ID: 19719828; Saito et al. 2017. PubMed ID: 28674365; F8 database: http://www.factorviii-db.org/advance_search.php). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.97	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs137852404; hg19: chrX-154197692; COSMIC: COSV64270281; COSMIC: COSV64270281;