rs28935203

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000132.4(F8):c.5096A>T(p.Tyr1699Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,156 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1699C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

F8
NM_000132.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.25

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 Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant X-154928694-T-A is Pathogenic according to our data. Variant chrX-154928694-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 10115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154928694-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F8	NM_000132.4 linkuse as main transcript	c.5096A>T	p.Tyr1699Phe	missense_variant	14/26	ENST00000360256.9	NP_000123.1	P00451-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F8	ENST00000360256.9 linkuse as main transcript	c.5096A>T	p.Tyr1699Phe	missense_variant	14/26	1	NM_000132.4	ENSP00000353393.4		P00451-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000554

AC:

AN:

180470

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65214

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361732

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

Cov.:

Alfa

AF:

0.0000480

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary factor VIII deficiency disease

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2023	Variant summary: F8 c.5096A>T (p.Tyr1699Phe) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 180470 control chromosomes. c.5096A>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 23926300). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Dec 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1990	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2022	Published functional studies demonstrate a damaging effect (Pezeshkpoor et al., 2019; van den Biggelaar et al., 2011); Also known as (p.Y1680F); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19473423, 24108539, 10368977, 1554716, 1898735, 21940821, 11857744, 8547094, 17958741, 30997536, 27378673, 33552050, 32791533, 32232366, 24452774, 21909383, 2105906, 18691168, 19302446, 33314404, 27629384, 32299908, 1908096) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2023	The F8 c.5096A>T; p.Tyr1699Phe variant (rs28935203), also known as Tyr1680Phe, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to FVIII database and references therein). This variant is reported in ClinVar (Variation ID: 10115), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. tyrosine at codon 1699 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.779). Based on available information, the p.Tyr1699Phe variant is considered to be pathogenic. References: Link to variant in FVIII variant database: http://www.factorviii-db.org/ -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2024

The c.5096A>T (p.Y1699F) alteration is located in exon 14 (coding exon 14) of the F8 gene. This alteration results from a A to T substitution at nucleotide position 5096, causing the tyrosine (Y) at amino acid position 1699 to be replaced by a phenylalanine (F). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/180470) total alleles studied, with 0 hemizygotes. The highest observed frequency was 0.001% (1/80944) of European (non-Finnish) alleles. This variant has been reported in multiple individuals with hemophilia A (Higuchi, 1990; Nance, 2013; Eckhardt, 2013; Pavlova, 2014; Nance, 2016). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing F8 function, this variant showed functionally abnormal results (van den Biggelaar, 2011; Pahl, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.53

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.78

Sift

Benign

0.036

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.74

MutPred

0.81

Loss of phosphorylation at Y1699 (P = 0.0194);

MVP

0.98

MPC

0.31

ClinPred

0.77

GERP RS

5.0

Varity_R

0.23

gMVP

0.93

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