rs28935203

chrX-154928694-T-AchrX-154928694-T-CchrX-154928694-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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. Y1699S) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.25

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]

ACMG classification

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 chrX-154928694-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2713111.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
F8	NM_000132.4	c.5096A>T	p.Tyr1699Phe	missense_variant	14/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.5096A>T	p.Tyr1699Phe	missense_variant	14/26	1	NM_000132.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000554 AC: 1 AN: 180470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65214

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: 1 AN: 1096156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361732

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.: 23

Alfa AF: 0.0000480 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

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/ -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.78
Sift	Benign	0.036	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.81		Loss of phosphorylation at Y1699 (P = 0.0194);
MVP		0.98
MPC		0.31
ClinPred		0.77	D
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

Other links and lift over

dbSNP: rs28935203; hg19: chrX-154156969;