NM_000132.4:c.3169G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. BS2PP3BA1

This summary comes from the ClinGen Evidence Repository: The c.3169G>A variant in F8 is a missense variant predicted to cause substitution of Glutamate by Lysine at amino acid 1057 (p.Glu1057Lys), affecting the B domain. The highest population minor allele frequency in gnomAD v2.1.1 is 0.006666 (99/14852 alleles) in the East Asian population with 28 hemizygotes, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1. The computational predictor REVEL gives a score of 0.651, which is above the CFD VCEP threshold of >=0.6, evidence that correlates with impact to F8 function (PP3). This variant was also identified in a proband with a diagnosis of hemophilia B and not hemophilia A, so the BS2 code was applied. In summary, this variant is classified as a benign for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel (version 1.0.0, released 10/5/2023): BA1, BS2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255144/MONDO:0010602/071

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00041 ( 8 hom. 160 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:5U:4B:1

Conservation

PhyloP100: 0.733

Publications

10 publications found

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 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

F8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP3

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

BS2

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

BA1

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.3169G>A	p.Glu1057Lys	missense	Exon 14 of 26	NP_000123.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
F8	ENST00000360256.9	TSL:1 MANE Select	c.3169G>A	p.Glu1057Lys	missense	Exon 14 of 26	ENSP00000353393.4
F8	ENST00000647125.1		n.*2835G>A		non_coding_transcript_exon	Exon 14 of 14	ENSP00000496062.1
F8	ENST00000647125.1		n.*2835G>A		3_prime_UTR	Exon 14 of 14	ENSP00000496062.1

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

112031

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00667

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000591

AC:

108

AN:

182664

AF XY:

0.000534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00707

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000614

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.000412

AC:

452

AN:

1095913

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

160

AN XY:

361351

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26365

American (AMR)

AF:

0.00

AC:

AN:

35173

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19368

East Asian (EAS)

AF:

0.0138

AC:

416

AN:

30187

South Asian (SAS)

AF:

0.000148

AC:

AN:

53979

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.000488

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

840217

Other (OTH)

AF:

0.000326

AC:

AN:

46011

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000250

AC:

AN:

112081

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34291

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30921

American (AMR)

AF:

0.00

AC:

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00669

AC:

AN:

3586

South Asian (SAS)

AF:

0.000370

AC:

AN:

2705

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53139

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000294

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary factor VIII deficiency disease (7)

not provided (1)

not specified (1)

Thrombophilia, X-linked, due to factor 8 defect (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.17

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

1.6

PhyloP100

0.73

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.99

REVEL

Pathogenic

0.65

Sift

Uncertain

0.010

Sift4G

Uncertain

0.035

Polyphen

0.68

Vest4

0.65

MVP

0.99

MPC

0.15

ClinPred

0.035

GERP RS

2.9

Varity_R

0.16

gMVP

0.72

Mutation Taster

=87/13

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over