rs782198570

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PP3_ModeratePP5BS2_Supporting

The NM_000132.4(F8):c.6623A>G(p.Gln2208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,208,893 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 5 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.73

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 4 ACMG points.

PM1

In a disulfide_bond (size 152) in uniprot entity FA8_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_000132.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant X-154861818-T-C is Pathogenic according to our data. Variant chrX-154861818-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 368117.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}. Variant chrX-154861818-T-C is described in Lovd as [Likely_pathogenic].

BS2

High Hemizygotes in GnomAdExome4 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 rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.6623A>G	p.Gln2208Arg	missense_variant	Exon 24 of 26	ENST00000360256.9	NP_000123.1	P00451-1
F8	NM_019863.3 link	c.218A>G	p.Gln73Arg	missense_variant	Exon 3 of 5		NP_063916.1	P00451-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.6623A>G	p.Gln2208Arg	missense_variant	Exon 24 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000330287.10 link	c.218A>G	p.Gln73Arg	missense_variant	Exon 3 of 5	1		ENSP00000327895.6	P00451-2
F8	ENST00000644698.1 link	c.356A>G	p.Gln119Arg	missense_variant	Exon 4 of 6			ENSP00000495706.1	A0A2R8Y707

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111647

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33825

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:

0.00

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

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183405

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67855

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097246

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

362620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000107

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000896

AC:

AN:

111647

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33825

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000425

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

F8-related disorder

Pathogenic:1

Jul 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The F8 c.6623A>G variant is predicted to result in the amino acid substitution p.Gln2208Arg. This variant also described using legacy nomenclature as p.Gln2189Arg; has been reported in multiple individuals with mild to moderate hemophilia A (Fernandez-Lopez et al. 2005. PubMed ID: 15921397; Markoff et al. 2009. PubMed ID: 19473423. Table S1; Silva Pinto et al. 2012. PubMed ID: 21645180; Bastida et al. 2016. PubMed ID: 26879396; F8 database: http://www.factorviii-db.org/index.php). Different missense variants in the same codon (c.6622C>G, p.Gln2208Glu; c.6623A>C, p.Gln2208Pro) have been reported in individuals with mild to moderate hemophilia A (Cid et al. 2007. PubMed ID: 17973853; Silva Pinto et al. 2012. PubMed ID: 21645180; F8 database: http://www.factorviii-db.org/index.php) suggesting that substitution of amino acid residue p.Gln2208 is not tolerated. This variant is reported in 0.0043% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-154090093-T-C). This variant is interpreted as pathogenic. -

Hereditary factor VIII deficiency disease

Pathogenic:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Uncertain:1

Dec 25, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

.;D;.

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.87

D;T;T

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

.;L;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.8

D;N;.

REVEL

Pathogenic

0.74

Sift

Benign

0.041

D;D;.

Sift4G

Benign

0.19

T;T;.

Polyphen

0.92

.;P;.

Vest4

0.39

MutPred

0.83

.;Gain of MoRF binding (P = 0.0657);.;

MVP

1.0

MPC

2.0

ClinPred

0.45

GERP RS

5.6

Varity_R

0.75

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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