rs137852388

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4BS2_Supporting

The NM_000132.4(F8):c.396A>C(p.Glu132Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,206,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 113 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00029 ( 0 hom. 108 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2B:4

Conservation

PhyloP100: -0.342

Publications

4 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000132.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 327 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 2.4669 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers, severe hemophilia A, moderately severe hemophilia A.

BP4

Computational evidence support a benign effect (MetaRNN=0.2800225).

BS2

High Hemizygotes in GnomAd4 at 5 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.396A>C	p.Glu132Asp	missense	Exon 4 of 26	NP_000123.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
F8	ENST00000360256.9	TSL:1 MANE Select	c.396A>C	p.Glu132Asp	missense	Exon 4 of 26	ENSP00000353393.4
F8	ENST00000423959.5	TSL:3	c.291A>C	p.Glu97Asp	missense	Exon 4 of 6	ENSP00000409446.1
F8	ENST00000453950.1	TSL:3	c.378A>C	p.Glu126Asp	missense	Exon 5 of 5	ENSP00000389153.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

112782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

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:

0.000394

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000176

AC:

AN:

182311

AF XY:

0.000179

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000357

Gnomad OTH exome

AF:

0.000445

GnomAD4 exome

AF:

0.000286

AC:

313

AN:

1093906

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

108

AN XY:

359350

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26314

American (AMR)

AF:

0.000227

AC:

AN:

35167

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.00

AC:

AN:

53974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.000495

AC:

AN:

4043

European-Non Finnish (NFE)

AF:

0.000349

AC:

293

AN:

838432

Other (OTH)

AF:

0.000196

AC:

AN:

45946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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

100

<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:

0.000204

AC:

AN:

112836

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31086

American (AMR)

AF:

0.000187

AC:

AN:

10719

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3610

South Asian (SAS)

AF:

0.00

AC:

AN:

2747

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000394

AC:

AN:

53339

Other (OTH)

AF:

0.00

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000155

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary factor VIII deficiency disease (4)

F8-related disorder (1)

Hemorrhage (1)

Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect (1)

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

0.20

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.10

CADD

Benign

9.4

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.70

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.28

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

0.73

PhyloP100

-0.34

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.95

REVEL

Pathogenic

0.68

Sift

Benign

0.34

Sift4G

Benign

0.55

Polyphen

0.67

Vest4

0.18

MutPred

0.72

Loss of disorder (P = 0.2076)

MVP

0.99

MPC

1.2

ClinPred

0.020

GERP RS

-0.35

Varity_R

0.38

gMVP

0.98

Mutation Taster

=68/32

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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