rs137852393

Positions:

• chrX-154993044-G-A

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.493C>T​(p.Pro165Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,715 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: F8 NM_000132.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.81

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000132.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant X-154993044-G-A is Pathogenic according to our data. Variant chrX-154993044-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154993044-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F8	NM_000132.4	c.493C>T	p.Pro165Ser	missense_variant	4/26	ENST00000360256.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F8	ENST00000360256.9	c.493C>T	p.Pro165Ser	missense_variant	4/26	1	NM_000132.4	P1
F8	ENST00000423959.5	c.388C>T	p.Pro130Ser	missense_variant	4/6	3
F8	ENST00000453950.1	c.475C>T	p.Pro159Ser	missense_variant	5/5	3
F8	ENST00000647125.1	c.*279C>T		3_prime_UTR_variant, NMD_transcript_variant	4/14

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183420 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097715 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363081

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor VIII deficiency disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 14, 2023

The F8 c.493C>T; p.Pro165Ser variant (rs137852393) is reported in the literature in an individual affected with severe hemophilia A (see F8 database and references therein). In vitro functional analyses demonstrate that individuals with this variant have factor VIII activity of <1% (F8 database). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another variant at this codon (c.494C>T, p.Pro165Leu) has been reported in individuals with hemophilia A and is considered pathogenic (Johnsen 2017). Computational analyses predict that this variant is deleterious (REVEL: 0.951). Based on available information, this variant is considered to be pathogenic. References: F8 database: https://f8-db.eahad.org/ 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;T;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.85
MutPred		0.82		Gain of catalytic residue at P165 (P = 0.0502);.;.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
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: rs137852393; hg19: chrX-154221319; COSMIC: COSV64278918;