rs28937285

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2_SupportingPS3PS4PP1_ModeratePP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.2215G>A (p.Glu739Lys) missense variant is absent from males in both gnomAD v2.1.1 and v3.1.1, meeting the PM2_Supporting criteria. The variant has a REVEL score of 0.614 (>0.6), meeting PP3 criteria. At least 13 patients with mild hemophilia A are reported in the literature and internal laboratory data meeting F8 phenotype criteria (PMID:24452774, 23711237, 21166991, 8547094, 16972227), which meets the PS4_Very strong and PP4_Moderate criteria. This variant has been labeled as an inverse discrepant variant, where the one-stage assays show lower factor VIII levels than the two-stage, or chromogenic, assays (EAHAD database; PMID:32232366). There were multiple related individuals across 6 different families reported that were genotyped, but their specific relation was not stated, so the PP1 was capped at the moderate weight to be conservative (PMID:24452774). In-vitro assays in COS-1 cells show FVIII-Glu739Lys results in lower FVIII:C in the mild range, as observed in patients with this variant and hemophilia A (PMID:30997536). 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: PS4_Very strong, PS3, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255139/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 3 hem. )

Consequence

F8
NM_000132.4 missense

Scores

4

5

8

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 2.71

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS3

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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.2215G>A	p.Glu739Lys	missense_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 link	c.2215G>A	p.Glu739Lys	missense_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4		P00451-1
F8	ENST00000647125.1 link	n.*1881G>A		non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1		A0A2R8Y7J7
F8	ENST00000647125 link	n.*1857G>A		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1		A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

2

AN:

111967

Hom.:

0

Cov.:

23

AF XY:

0.00

AC XY:

0

AN XY:

34151

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

6

AN:

1097333

Hom.:

0

Cov.:

32

AF XY:

0.00000827

AC XY:

3

AN XY:

362753

show subpopulations

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

2

AN:

111967

Hom.:

0

Cov.:

23

AF XY:

0.00

AC XY:

0

AN XY:

34151

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000640

Hom.:

0

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:2

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2024

ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2215G>A (p.Glu739Lys) missense variant is absent from males in both gnomAD v2.1.1 and v3.1.1, meeting the PM2_Supporting criteria. The variant has a REVEL score of 0.614 (>0.6), meeting PP3 criteria. At least 13 patients with mild hemophilia A are reported in the literature and internal laboratory data meeting F8 phenotype criteria (PMID: 24452774, 23711237, 21166991, 8547094, 16972227), which meets the PS4_Very strong and PP4_Moderate criteria. This variant has been labeled as an inverse discrepant variant, where the one-stage assays show lower factor VIII levels than the two-stage, or chromogenic, assays (EAHAD database; PMID: 32232366). There were multiple related individuals across 6 different families reported that were genotyped, but their specific relation was not stated, so the PP1 was capped at the moderate weight to be conservative (PMID: 24452774). In-vitro assays in COS-1 cells show FVIII-Glu739Lys results in lower FVIII:C in the mild range, as observed in patients with this variant and hemophilia A (PMID: 30997536). 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: PS4_Very strong, PS3, PP1_Moderate, PP4_Moderate, PP3, PM2_Supporting. -

F8-related disorder

Pathogenic:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The F8 c.2215G>A variant is predicted to result in the amino acid substitution p.Glu739Lys. This variant (aka. p.Glu720Lys) has been reported in multiple individuals with hemophilia A (Schwaab et al. 1995. PubMed ID: 8547094; Factor VIII (F8) Gene Variant Database: https://www.factorviii-db.org/index.php). This variant is reported in 0.0092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.38

D

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

17

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D

FATHMM_MKL

Benign

0.24

N

LIST_S2

Benign

0.79

T

M_CAP

Pathogenic

0.42

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Uncertain

0.44

D

MutationAssessor

Benign

1.5

L

PrimateAI

Benign

0.40

T

PROVEAN

Benign

-2.3

N

REVEL

Uncertain

0.61

Sift

Uncertain

0.022

D

Sift4G

Benign

0.18

T

Polyphen

0.91

P

Vest4

0.65

MutPred

0.81

Gain of ubiquitination at E739 (P = 0.0109);

MVP

1.0

MPC

0.082

ClinPred

0.67

D

GERP RS

5.2

Varity_R

0.46

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28937285; hg19: chrX-154159850;