rs137852417

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R550H) has been classified 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, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.99

Publications

8 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: Pathogenic. The variant received 17 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, 3 uncertain in NM_000132.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154957060-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10225.Status of the report is reviewed_by_expert_panel, 3 stars.

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.

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/Likely_pathogenic. ClinVar VariationId is 10223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F8	NM_000132.4 link	c.1648C>T	p.Arg550Cys	missense_variant	Exon 11 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.1648C>T	p.Arg550Cys	missense_variant	Exon 11 of 26	1	NM_000132.4	ENSP00000353393.4	P00451-1
F8	ENST00000647125.1 link	n.*1524C>T		non_coding_transcript_exon_variant	Exon 12 of 14			ENSP00000496062.1	A0A2R8Y7J7
F8	ENST00000647125.1 link	n.*1524C>T		3_prime_UTR_variant	Exon 12 of 14			ENSP00000496062.1	A0A2R8Y7J7

Frequencies

GnomAD3 genomes

AF:

0.00000899

AC:

AN:

111199

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:

0.00

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

African (AFR)

AF:

0.00

AC:

AN:

26347

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.00

AC:

AN:

54073

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839657

Other (OTH)

AF:

0.00

AC:

AN:

45996

GnomAD4 genome

AF:

0.00000899

AC:

AN:

111199

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33401

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30551

American (AMR)

AF:

0.00

AC:

AN:

10422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5929

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

53032

Other (OTH)

AF:

0.00

AC:

AN:

1500

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000166

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

May 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The F8 c.1648C>T; p.Arg550Cys variant (rs137852417, ClinVar Variation ID: 10223) is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to Factor VIII database and references therein, David 2006, Green 2008, Johnsen 2017, Lu 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.749). Additionally, other amino acid substitutions at this codon (His, Pro, Leu, Gly) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://f8-db.eahad.org/ David D et al. The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. Haematologica. 2006;91(6):840-843. PMID: 16769589. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008;143(1):115-128. PMID: 18691168. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017;1(13):824-834. PMID: 29296726. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018;24(2):291-298. PMID: 29381227. -

Hereditary factor VIII deficiency disease

Pathogenic:1

Jul 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mild hemophilia A

Pathogenic:1

Apr 10, 2024

Versiti Diagnostic Laboratories, Versiti, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.0

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

Mutation Taster

=9/91

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over