rs137852428

Variant names:

• chrX-154953961-G-A
• rs137852428
• NM_000132.4:c.1834C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS4 PS2 PP1_Strong PP3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1834C>T (p.Arg612Cys) variant is present in 3 hemizygotes in gnomAD v2.1.1, so PM2_Supporting in not met. The REVEL score of 0.88 which meets PP3 criteria (threshold >0.6). Thirty-two patients were reported with mild-moderate hemophilia A in a single publication and over 100 individuals were identified in the My Life Our Future Cohort, meeting F8 phenotype criteria for PP4_Moderate and PS4_Very strong (PMID:18691168, 29296726). This variant has been associated with mostly mild, but also moderate and severe, hemophilia A with and without inhibitors to factor replacement therapies. This may be in part because the variant has also been associated with discrepant factor VIII activity levels, with chromogenic assays (two-stage) being 2-fold lower than one stage assays (EAHAD database; PMID:32232366). The variant has been reported to segregate with hemophilia A in greater than 6 meioses across two families (PP1_Strong; PMID:9292523). This variant has also been found to have at least one de novo occurrence in the mother of a proband, where the proband was found to have the unaffected maternal grandfather's allele via haplotype analysis (PS2; PMID:9292523). Additionally, this variant has been reported in patients with and without a history of inhibitors to factor replacement products (EAHAD database). 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 F8: PS2, PS4_Very strong, PP1_Strong, PP3 and PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255129/MONDO:0010602/071

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 2.73
• Publications: 21 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 15 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	NM_000132.4	MANE Select	c.1834C>T	p.Arg612Cys	missense	Exon 12 of 26	NP_000123.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F8	ENST00000360256.9	TSL:1 MANE Select	c.1834C>T	p.Arg612Cys	missense	Exon 12 of 26	ENSP00000353393.4
	F8	ENST00000647125.1		n.*1710C>T		non_coding_transcript_exon	Exon 13 of 14	ENSP00000496062.1
	F8	ENST00000647125.1		n.*1710C>T		3_prime_UTR	Exon 13 of 14	ENSP00000496062.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111816 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000218 AC: 4 AN: 183438 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097783 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363141

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

American (AMR) AF: 0.0000852 AC: 3 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54135

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000832 AC: 7 AN: 841729

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111816 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 33994

African (AFR) AF: 0.0000325 AC: 1 AN: 30727

American (AMR) AF: 0.00 AC: 0 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.0000269 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary factor VIII deficiency disease (5)
3	-	-	not provided (3)
1	-	-	Familial aortopathy (1)
1	-	-	Hereditary factor IX deficiency disease (1)
1	-	-	Thrombophilia, X-linked, due to factor 8 defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.85		Loss of helix (P = 0.0033)
MVP		1.0
MPC		1.8
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs137852428; hg19: chrX-154182236; COSMIC: COSV64269271;