X-154930621-C-T

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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 0.733

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.3169G>A	p.Glu1057Lys	missense_variant	Exon 14 of 26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.3169G>A	p.Glu1057Lys	missense_variant	Exon 14 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*2835G>A		non_coding_transcript_exon_variant	Exon 14 of 14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125 link	n.*2811G>A		3_prime_UTR_variant	Exon 14 of 14			ENSP00000496062.1	A0A2R8Y7J7

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

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26365

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35173

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19368

Gnomad4 EAS exome

AF:

0.0138

AC:

416

AN:

30187

Gnomad4 SAS exome

AF:

0.000148

AC:

AN:

53979

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40511

Gnomad4 NFE exome

AF:

0.0000131

AC:

AN:

840217

Gnomad4 Remaining exome

AF:

0.000326

AC:

AN:

46011

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00669

AC:

0.00669269

AN:

0.00669269

Gnomad4 SAS

AF:

0.000370

AC:

0.000369686

AN:

0.000369686

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000565

AC:

0.0000564557

AN:

0.0000564557

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:4Uncertain:2

Aug 05, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PS3, PP2, PP3, PP5; Variant was found in heterozygous state. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1057Lys (NM_000132.3 c.3169G>A) variant in F8 has been reported hemizygously in three males with Hemophilia A and low factor VIII levels, though one of these individuals carried a second pathogenic variant (Higuchi 1991, Chan 1996, Huang 2009). This variant has also been reported in ClinVar (Variation ID#10251). This variant has been identified in 0.7% (95/13902) of East Asian chromosomes, including 1 homozygote and 29 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28933673). In vitro functional studies provide some evidence that the p.Glu1057Lys variant may impact protein function (Pahl 2014); however, these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Glu1057Lys variant is uncertain. -

Apr 16, 2013

UCLA Clinical Genomics Center, UCLA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with haemophilia A (MIM#306700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (71 heterozygotes, 1 homozygote, 36 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated B domain (PMID: 24108539). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in at least three individuals with haemophilia A (PMIDs: 1924291, 19719548, 30913330). It has also been reported as polymorphism in a haemophilia A cohort, and as hemizygous in an individual with haemophilia B (PMIDs: 18479430, 29296726). It has been reported as both likely pathogenic and uncertain significance in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Authors of a functional study using transfected HEK cells described that the variant protein had mildly decreased factor VIII activity and significantly reduced thermostability (PMID: 24108539), however their raw data was incomplete and not convincing. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Thrombophilia, X-linked, due to factor 8 defect

Pathogenic:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: F8 c.3169G>A (p.Glu1057Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 182664 control chromosomes, predominantly at a frequency of 0.0071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote and 36 hemizygotes across the subpopulations. This frequency is not significantly higher than estimated for a pathogenic variant in F8 causing Factor VIII Deficiency (Hemophilia A) (0.00059 vs 0.0098), allowing no conclusion about variant significance. c.3169G>A has been reported in the literature in individuals affected with Factor VIII Deficiency (Hemophilia A) without strong evidence of causality (e.g. Higuchi_1991b, Chan_1996, Hwang_2009, Luu_2019, Li_2020, Chen_2021). These reports do not provide unequivocal conclusions about association of the variant with Factor VIII Deficiency (Hemophilia A). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in reduced FVIII activity and antigen values in HEK293T cells (Pahl_2014). The following publications have been ascertained in the context of this evaluation (PMID: 1924291, 8639447, 19719548, 29296726, 32190902, 34272389, 33706050, 33245802, 35770352, 30913330, 24108539). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2), likely pathogenic (n=1) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Jun 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2, PS3_supporting, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

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

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)

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over