rs137852417

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_000132.4(F8):c.1648C>T(p.Arg550Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,680 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.99

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 Likely_pathogenic. Variant got 6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant X-154957061-G-A is Pathogenic according to our data. Variant chrX-154957061-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10223.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154957061-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154957061-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 link	c.1648C>T	p.Arg550Cys	missense_variant	11/26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
F8	ENST00000360256.9 link	c.1648C>T	p.Arg550Cys	missense_variant	11/26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*1524C>T		non_coding_transcript_exon_variant	12/14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125.1 link	n.*1524C>T		3_prime_UTR_variant	12/14			ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.00000899

AC:

AN:

111199

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33401

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095481

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360893

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000899

AC:

AN:

111199

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33401

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:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000166

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1992

- -

Mild hemophilia A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Versiti Diagnostic Laboratories, Versiti, Inc

Apr 10, 2024

The missense variant F8 c.1648C>T, p.Arg550Cys (p.R550C; legacy p.R531C) in exon 11 changes amino acid arginine at codon 550 to cysteine. The arginine at this residue is fairly well conserved among species. This amino acid change occurs at the interface of the A1 and A2 domains. Pathogenic variants in F8 are associated with X-linked hemophilia A characterized by mild to severe bleeding due to a quantitative or qualitative deficiency in factor VIII. This sequence variant has been previously reported in patients with mild to moderate hemophilia A, both with and without the development of inhibitors (PMID:1924291; PMID:8547094; PMID:16769589; PMID:17286776; PMID:20331753; PMID:23926300; PMID:29296726). Patients carrying this variant show discrepancy between 1-stage and 2-stage factor VIII activity assays, with a lower measurement recorded with 2-stage assay (PMID:17286776). This variant was observed in 6 males and 3 females within our laboratory cohort. All 6 males within our laboratory cohort had clot based factor VIII activity levels consistent with moderate or mild hemophilia A; 3 out of 6 males had VWD 2N ruled out by either a 2N binding assay or by negative next generation sequencing. The minor allele frequency of this variant in the general population is 0.000008993 (GnomAD v3). No functional data is available for this variant. In silico computational evidence (REVEL) predicts the variant to be damaging (>=0.644 ); however, computational evidence alone is not sufficient to classify a variant. Different variants causing a change at the same amino acid (c.1648C>G, p.R550G; c.1649G>A, p.R550H; c.1649G>T, p.R550L; c.1649G>C, p.R550P) have also been reported in patients with mild to severe hemophilia A (PMID:1924291; PMID:19473423; PMID:8547094; PMID:11157485; PMID:18179574; PMID:29296726). Functional studies of the alternate p.R550H variant using recombinant protein demonstrated a similar discrepant activity between 1-stage and 2-stage assays and showed an increased rate of A2 subunit dissociation correlating with inactivation of FVIIIa (PMID:11157485). In summary, the collective evidence supports F8 c.1648C>T, p.Arg550Cys as a pathogenic variant for mild to moderate hemophilia A. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

2.9

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.9

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.60

MutPred

0.94

Loss of sheet (P = 0.0181);

MVP

1.0

MPC

1.9

ClinPred

0.99

GERP RS

1.9

Varity_R

0.95

gMVP

0.99

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