rs137852388

Positions:

chrX-154993141-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BS2_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:3

Conservation

PhyloP100: -0.342

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 Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000132.4

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4 linkuse as main transcript	c.396A>C	p.Glu132Asp	missense_variant	4/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.396A>C	p.Glu132Asp	missense_variant	4/26	1	NM_000132.4	P1	P00451-1
F8	ENST00000423959.5 linkuse as main transcript	c.291A>C	p.Glu97Asp	missense_variant	4/6	3
F8	ENST00000453950.1 linkuse as main transcript	c.378A>C	p.Glu126Asp	missense_variant	5/5	3
F8	ENST00000647125.1 linkuse as main transcript	c.*182A>C		3_prime_UTR_variant, NMD_transcript_variant	4/14

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

112782

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34914

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

GnomAD3 exomes

AF:

0.000176

AC:

AN:

182311

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

66937

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000349

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000204

AC:

AN:

112836

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

34978

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000187

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000394

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000211

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:1Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 31, 2020	The F8:c.396A>C variant is predicted to result in a missense change from glutamic acid to aspartic acid at amino acid 132 (p.Glu132Asp, formerly known as p.Glu113Asp). This variant has an allele frequency of 0.0003158 in non-Finnish European controls (gnomAD 2.1.2). This is significantly higher than expected for a pathogenic variant, given the incidence of haemophilia A (1/4000 males, PMID 32497379), and the proportion of symptomatic haemophilia A attributable to missense variation (17% severe and 81% non-severe haemophilia A, PMID 35770352) (BS1). This variant has been seen in cis to p.Arg612Cys (formerly p.Arg593Cys) in 22 Slovenian patients with Haemophilia A. In this study, an affected patient was identified with the less common p.Arg612Cys alone, but no patients had only F8:c.396A>C. This variant was also reported in cis to a frameshift variant in severe HA (PMID 11442643) (BP2). F8:c.396A>C has been reported in five patients with haemophilia A, prior to the availability of allele frequency databases (PMID 7984443, 19473423, 17445092, 15921397, 16173970), with 5 further unpublished cases on the EAHAD database. However, studies after the development of ACMG variant classification consider this variant benign or of unknown significance (eg. PMID 36007526, 34272389). In a multicentre analysis of US haemophilia treatment centres, with 8976 haemophilia A cases and 2358 haemophilia B cases, this variant was detected in haemophilia B patients and regarded as non-reportable (PMID 35770352). Locally, this variant was identified in two hemizygous males with no clinical or biochemical evidence of haemophilia A (BP5). -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 08, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hemophilia A (MIM#306700). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals with hemophilia A vary in severity ranging from mild to severe depending on the plasma levels of coagulation factor VIII (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Hemophilia A. This variant is present in gnomAD (v2: 1 homozygote, 12 hemizygotes) and has been identified in a number of unaffected hemizygotes in a newborn screening study of ~454000 UK biobank subjects (PMID:36007526). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated A1 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The variant p.(Glu132Ala) has a larger amino acid change (Grantham score = 107) and has been reported once in a patient with mild hemophilia A (PMID: 17445092). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as pathogenic, likely pathogenic and likely benign in ClinVar by other clinical laboratories. In the literature, it has been reported in families with mild hemophilia A (PMID: 22958177; 15921397) however in other families it has been reported in cis with other known pathogenic F8 variants where the pathogenicity of this variant could not be determined (PMID: 9603440; 11442643; 26057490). Internal data shows that individuals with this variant had mildly reduced to normal levels of factor VIII and none reported any history of excessive bleeding. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

F8-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

The F8 c.396A>C variant is predicted to result in the amino acid substitution p.Glu132Asp. Using legacy nomenclature, this variant is also referred to as p.Glu113Asp). This variant has been reported to be causative for Hemophilia A (Freson et al. 1998. PubMed ID: 9603440; Markoff et al. 2009. PubMed ID: 19473423; Trampuš Bakija et al. 2015. PubMed ID: 26057490; Supplemental Table 2, Baz et al. 2021. PubMed ID: 34272389). Of note, another variant impacting the same amino acid has also been reported in individuals with Hemophilia A [c.395A>C (p.Glu132Ala, aka p.Glu113Ala using legacy nomenclature), Repesse et al. 2007. PubMed ID: 17445092]. This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

Thrombophilia, X-linked, due to factor 8 defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

F8: PM1, PM5 -

Hemorrhage

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.10

CADD

Benign

9.4

DANN

Benign

0.97

DEOGEN2

Uncertain

0.70

D;T;T

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.82

T;D;T

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

0.73

N;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.95

N;N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.55

T;.;.

Polyphen

0.67

P;B;.

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

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

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