rs137852405

chrX-154969405-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000132.4(F8):c.935T>C(p.Phe312Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,091 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.89

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-154969405-A-G is Pathogenic according to our data. Variant chrX-154969405-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154969405-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.935T>C	p.Phe312Ser	missense_variant	7/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.935T>C	p.Phe312Ser	missense_variant	7/26	1	NM_000132.4	P1
F8	ENST00000647125.1	c.*811T>C		3_prime_UTR_variant, NMD_transcript_variant	8/14

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098091 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363477

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

Bravo AF: 0.000234

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2023	Variant summary: F8 c.935T>C (p.Phe312Ser) results in a non-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 was absent in 183329 control chromosomes (gnomAD). c.935T>C has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (examples: Higuchi_1991, Miller_2012, Downes_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 22103590, 1908096). Two 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, no assertion criteria provided	literature only	OMIM	Aug 15, 1991	- -

Hereditary factor IX deficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 19, 2023

The F8 c.935T>C; p.Phe312Ser variant (rs137852405), also known as p.Phe293Ser in traditional nomenclature, is reported in the literature in numerous individuals affected with mild hemophilia A (Higuchi 1991, Johnsen 2017, Liu 1998, Miller 2012). This variant is reported in ClinVar (Variation ID: 10196), but it is absent from the Genome Aggregation Database indicating it is not a common polymorphism. The phenylalanine at codon 312 is moderately conserved, and modeling approaches suggest this variant disrupts tertiary structure and hydrogen bonding patterns in the mature protein (Liu 1998, Markoff 2009). Further, this variant occurs in a domain involved in interaction with the chaperone protein BiP and cellular studies suggest it results in impaired secretion (Swaroop 1997). Based on available information, the p.Phe312Ser variant is considered to be pathogenic. References: Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. PMID: 1908096. 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 May 18;1(13):824-834. PMID: 29296726. Liu M et al. A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins. Br J Haematol. 1998 Dec;103(4):1051-60. PMID: 9886318. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. PMID: 19473423. Miller CH et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012 May;18(3):375-82. PMID: 22103590. Swaroop M et al. Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII. J Biol Chem. 1997 Sep 26;272(39):24121-4. PMID: 9305856. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.65	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.86
Sift	Benign	0.20	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.89		Gain of disorder (P = 0.0123);
MVP		1.0
MPC		2.2
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.86
gMVP		1.0

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: rs137852405; hg19: chrX-154197680;